Metalloenzyme inhibitor compounds

ABSTRACT

The instant invention describes compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.

BACKGROUND

Living organisms have developed tightly regulated processes thatspecifically import metals, transport them to intracellular storagesites and ultimately transport them to sites of use. One of the mostimportant functions of metals such as zinc and iron in biologicalsystems is to enable the activity of metalloenzymes. Metalloenzymes areenzymes that incorporate metal ions into the enzyme active site andutilize the metal as a part of the catalytic process. More thanone-third of all characterized enzymes are metalloenzymes.

The function of metalloenzymes is highly dependent on the presence ofthe metal ion in the active site of the enzyme. It is well recognizedthat agents which bind to and inactivate the active site metal iondramatically decrease the activity of the enzyme. Nature employs thissame strategy to decrease the activity of certain metalloenzymes duringperiods in which the enzymatic activity is undesirable. For example, theprotein TIMP (tissue inhibitor of metalloproteases) binds to the zincion in the active site of various matrix metalloprotease enzymes andthereby arrests the enzymatic activity. The pharmaceutical industry hasused the same strategy in the design of therapeutic agents. For example,the azole antifungal agents fluconazole and voriconazole contain a1-(1,2,4-triazole) group that binds to the heme iron present in theactive site of the target enzyme lanosterol demethylase and therebyinactivates the enzyme. Another example includes the zinc-bindinghydroxamic acid group that has been incorporated into most publishedinhibitors of matrix metalloproteinases and histone deacetylases.Another example is the zinc-binding carboxylic acid group that has beenincorporated into most published angiotensin-converting enzymeinhibitors.

In the design of clinically safe and effective metalloenzyme inhibitors,use of the most appropriate metal-binding group for the particulartarget and clinical indication is critical. If a weakly bindingmetal-binding group is utilized, potency may be suboptimal. On the otherhand, if a very tightly binding metal-binding group is utilized,selectivity for the target enzyme versus related metalloenzymes may besuboptimal. The lack of optimal selectivity can be a cause for clinicaltoxicity due to unintended inhibition of these off-targetmetalloenzymes. One example of such clinical toxicity is the unintendedinhibition of human drug metabolizing enzymes such as CYP2C9, CYP2C19and CYP3A4 by the currently-available azole antifungal agents such asfluconazole and voriconazole. It is believed that this off-targetinhibition is caused primarily by the indiscriminate binding of thecurrently utilized 1-(1,2,4-triazole) to iron in the active site ofCYP2C9, CYP2C19 and CYP3A4. Another example of this is the joint painthat has been observed in many clinical trials of matrixmetalloproteinase inhibitors. This toxicity is considered to be relatedto inhibition of off-target metalloenzymes due to indiscriminate bindingof the hydroxamic acid group to zinc in the off-target active sites.

Therefore, the search for metal-binding groups that can achieve a betterbalance of potency and selectivity remains an important goal and wouldbe significant in the realization of therapeutic agents and methods toaddress currently unmet needs in treating and preventing diseases,disorders and symptoms thereof.

BRIEF SUMMARY OF THE INVENTION

The invention is directed towards compounds (e.g., any of thosedelineated herein), methods of modulating activity of metalloenzymes,and methods of treating diseases, disorders or symptoms thereof. Themethods can comprise the compounds herein.

It is understood that the embodiments of the invention discussed belowwith respect to the preferred variable selections can be taken alone orin combination with one or more embodiments, or preferred variableselections, of the invention, as if each combination were explicitlylisted herein.

A compound of formula (I), or salt, solvate, hydrate or prodrug thereof,wherein:

R₁ is halo;

R₂ is halo;

each R₃ is independently cyano, haloalkyl, alkoxy, halo, haloalkoxy,hydroxy, amino, —NR₆R₉, —SR₁₀, —C(O)R₁₀, optionally substitutedhaloalkyl, optionally substituted arylalkoxy, —C(O)NR₆R₇,—CH(OH)-haloalkyl, optionally substituted alkyl, hydroxyalkyl,optionally substituted alkoxyalkyl, isocyano, cycloalkylaminocarbonyl,optionally substituted aryloxyalkyl, optionally substitutedarylalkylthio, haloalkylthio, optionally substituted arylalkylsulfonyl,optionally substituted arylalkylsulfinyl, optionally substitutedheteroarylalkoxy, or haloalkylcarbonyl;

n is 0, 1, 2 or 3;

R₄ is aryl optionally substituted with 0, 1, 2 or 3 independent R₈;

R₅ is H, alkyl, phosphato, phosphito, alkoxyphosphato, or —C(O)alkyloptionally substituted with amino;

R₆ is independently H or alkyl;

R₇ is independently H, optionally substituted alkyl, optionallysubstituted haloalkyl, or optionally substituted arylalkyl;

each R₈ is independently cyano, haloalkyl, alkoxy, halo, or haloalkoxy;

each R₉ is independently H, alkyl, —C(O)alkyl, —C(O)H, —C(O)haloalkyl,or optionally substituted haloalkyl;

each R₁₀ is independently H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted arylalkyl;

Ar₂ is

R₁₁ is optionally substituted phenyl, optionally substituted alkyl,optionally substituted thienyl, pyrrolyl, furanyl, optionallysubstituted pyridyl, —CH(OH)-alkyl, —CH(OH)-haloalkyl, optionallysubstituted arylalkyl, optionally substituted aryloxyalkyl, haloalkyl,haloalkoxyalkyl, optionally substituted indolyl, optionally substitutedbenzofuranyl, heterocycloalkyl, or

R₁₂ is R₄, —C(O)R₄, —C(O)R₇, —SO₂R₄;

MBG is optionally substituted tetrazolyl, optionally substitutedtriazolyl, optionally substituted oxazolyl, optionally substitutedpyrimidinyl, optionally substituted thiazolyl, or optionally substitutedpyrazolyl.

Another aspect is a compound of formula (I), or salt, solvate, hydrateor prodrug thereof, wherein:

R₁ is halo;

R₂ is halo;

each R₃ is independently cyano, haloalkyl, alkoxy, halo, haloalkoxy,hydroxy, amino, —NR₆R₉, —SR₁₀, —C(O)R₁₀, optionally substitutedhaloalkyl, optionally substituted arylalkoxy, C(O)NR₆R₇,—CH(OH)-haloalkyl, optionally substituted alkyl, hydroxyalkyl,optionally substituted alkoxyalkyl, isocyano, cycloalkylaminocarbonyl,optionally substituted aryloxyalkyl, optionally substitutedarylalkylthio, haloalkylthio, optionally substituted arylalkylsulfonyl,optionally substituted arylalkylsulfinyl, optionally substitutedheteroarylalkoxy, optionally substituted arylthioalkyl, orhaloalkylcarbonyl;

n is 0, 1, 2 or 3;

R₄ is aryl optionally substituted with 0, 1, 2 or 3 independent R₈;

R₅ is H, alkyl, phosphato, phosphito, alkoxyphosphato, or —C(O)alkyloptionally substituted with 1 or 2 amino;

R₆ is independently H or alkyl;

R₇ is independently H, optionally substituted alkyl, optionallysubstituted haloalkyl, or optionally substituted arylalkyl;

each R₈ is independently cyano, haloalkyl, alkoxy, halo, or haloalkoxy;

each R₉ is independently H, alkyl, —C(O)alkyl, —C(O)H, —C(O)haloalkyl,optionally substituted arylalkyl, or optionally substituted haloalkyl;

each R₁₀ is independently H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heterocycloalkyl, or optionallysubstituted arylalkyl;

Ar₂ is

R₁₁ is optionally substituted phenyl, optionally substituted alkyl,optionally substituted thienyl, pyrrolyl, furanyl, optionallysubstituted pyridyl, —CH(OH)-alkyl, —CH(OH)-haloalkyl, optionallysubstituted arylalkyl, optionally substituted aryloxyalkyl, haloalkyl,haloalkoxyalkyl, optionally substituted indolyl, optionally substitutedbenzofuranyl, heterocycloalkyl, or

R₁₂ is R₄, —C(O)R₄, —C(O)R₇, —SO₂R₄;

MBG is optionally substituted tetrazolyl, optionally substitutedtriazolyl, optionally substituted oxazolyl, optionally substitutedpyrimidinyl, optionally substituted thiazolyl, or optionally substitutedpyrazolyl.

Another aspect is a compound of the formulae herein, wherein R₁ isfluoro.

Another aspect is a compound of the formulae herein, wherein R₂ isfluoro.

Another aspect is a compound of the formulae herein, wherein R₁ and R₂are fluoro.

Another aspect is a compound of the formulae herein, wherein R₄ isphenyl optionally substituted with 0, 1, 2 or 3 independent R₈.

Another aspect is a compound of the formulae herein, wherein R₄ isphenyl optionally substituted with 0, 1, 2 or 3 independent halo.

Another aspect is a compound of the formulae herein, wherein R₄ isphenyl optionally substituted with 0, 1, 2 or 3 independent fluoro.

Another aspect is a compound of the formulae herein, wherein R₄ is2,4-difluorophenyl.

Another aspect is a compound of the formulae herein, wherein R₅ is H.

Another aspect is a compound of the formulae herein, wherein R₅ is aminosubstituted acyl.

Another aspect is a compound of the formulae herein, wherein R₅ is—C(O)alkyl optionally substituted with 1 or 2 amino.

Another aspect is a compound of the formulae herein, wherein R₅ isphosphato.

Another aspect is a compound of the formulae herein, wherein:

-   -   R₁ is fluoro;    -   R₂ is fluoro;    -   R₄ is 2,4-difluorophenyl;    -   R₅ is H;    -   Ar₂ is

and

-   -   MBG is 1-tetrazolyl.

Another aspect is a compound of the formulae herein, wherein:

-   -   R₁ is fluoro;    -   R₂ is fluoro;    -   R₄ is 2,4-difluorophenyl;    -   R₅ is H;    -   Ar₂ is

-   -   MBG is 1-tetrazolyl;    -   R₁₁ is phenyl, thienyl, arylalkyl, aryloxyalkyl, each optionally        substituted with 0, 1, 2, or 3 independent R₃;    -   each R₃ is independently cyano, haloalkyl, halo, haloalkoxy,        optionally substituted arylalkoxy, haloalkylaminocarbonyl,        optionally substituted arylalkylaminocarbonyl; and    -   n is 1 or 2.

Another aspect is a compound of the formulae herein, wherein:

-   -   R₁ is fluoro;    -   R₂ is fluoro;    -   R₄ is 2,4-difluorophenyl;    -   R₅ is H;    -   Ar₂ is

-   -   MBG is 1-tetrazolyl;    -   R₁₁ is phenyl, thienyl, arylalkyl, aryloxyalkyl, each optionally        substituted with 0, 1, 2, or 3 independent R₃;    -   each R₃ is independently cyano, haloalkyl, halo, haloalkoxy,        arylalkoxy optionally substituted with halo, cyano, haloalkyl,        or haloalkoxy, haloalkylaminocarbonyl, arylalkylaminocarbonyl        optionally substituted with halo, cyano, or haloalkyl; and n is        1 or 2.

Another aspect is a compound of the formulae herein, wherein:

-   -   R₁ is fluoro;    -   R₂ is fluoro;    -   R₄ is 2,4-difluorophenyl;    -   R₅ is H;    -   Ar₂ is

-   -   MBG is 1-tetrazolyl;    -   R₁₁ is phenyl, thienyl, arylalkyl, aryloxyalkyl, each optionally        substituted with 0, 1, 2, or 3 independent R₃;    -   each R₃ is independently —NR₆R₉, haloalkylcarbonyl, alkoxyalkyl,        hydroxyalkyl, acyl, haloalkylthio, —CH(OH)-haloalkyl, alkyl,        alkoxy, cyano, haloalkyl, halo, haloalkoxy, arylalkoxy        optionally substituted with halo, cyano, haloalkyl, or        haloalkoxy, haloalkylaminocarbonyl, arylalkylaminocarbonyl        optionally substituted with halo, cyano, haloalkoxy, or        haloalkyl; and    -   n is 1 or 2.

Another aspect is a compound of the formulae herein, wherein:

-   -   R₁ is fluoro;    -   R₂ is fluoro;    -   R₄ is 2,4-difluorophenyl;    -   R₅ is H;    -   Ar₂ is

-   -   MBG is 1-tetrazolyl;    -   R₁₁ is phenyl, thienyl, arylalkyl, aryloxyalkyl, each optionally        substituted with 0, 1, 2, or 3 independent R₃;    -   each R₃ is independently cyano, haloalkyl, halo, haloalkoxy,        optionally substituted arylalkoxy, haloalkylaminocarbonyl,        optionally substituted arylalkylaminocarbonyl; and    -   n is 1.

Another aspect is a compound of the formulae herein, wherein:

-   -   R₁ is fluoro;    -   R₂ is fluoro;    -   R₄ is 2,4-difluorophenyl;    -   R₅ is H;    -   Ar₂ is

-   -   MBG is 1-tetrazolyl;    -   R₁₁ is phenyl optionally substituted with 0, 1, 2, or 3        independent R₃;    -   each R₃ is independently cyano, haloalkyl, halo; and    -   n is 1 or 2.

Another aspect is a compound of the formulae herein, wherein:

-   -   R₁ is fluoro;    -   R₂ is fluoro;    -   R₄ is 2,4-difluorophenyl;    -   R₅ is H;    -   Ar₂ is

-   -   MBG is 1-tetrazolyl;    -   R₁₁ is phenyl optionally substituted with 0, 1, 2, or 3        independent R₃;    -   each R₃ is independently —NR₆R₉, haloalkylcarbonyl, alkoxyalkyl,        hydroxyalkyl, acyl, haloalkylthio, —CH(OH)-haloalkyl, alkyl,        alkoxy, cyano, haloalkyl, halo, haloalkoxy, arylalkoxy        optionally substituted with halo, cyano, haloalkyl, or        haloalkoxy, haloalkylaminocarbonyl, arylalkylaminocarbonyl        optionally substituted with halo, cyano, haloalkoxy, or        haloalkyl; and    -   n is 1 or 2.

Another aspect is a compound of the formulae herein, wherein:

-   -   R₁ is fluoro;    -   R₂ is fluoro;    -   R₄ is 2,4-difluorophenyl;    -   R₅ is H;

Ar₂ is

-   -   MBG is 1-tetrazolyl;    -   R₁₁ is thienyl optionally substituted with 0, 1, 2, or 3        independent R₃;    -   each R₃ is independently haloalkylaminocarbonyl, optionally        substituted arylalkylaminocarbonyl; and    -   n is 1 or 2.

Another aspect is a compound of the formulae herein, wherein:

-   -   R₁ is fluoro;    -   R₂ is fluoro;    -   R₄ is 2,4-difluorophenyl;    -   R₅ is H;    -   Ar₂ is

-   -   MBG is 1-tetrazolyl;    -   R₁₁ is thienyl optionally substituted with 0, 1, 2, or 3        independent R₃;    -   each R₃ is independently haloalkylaminocarbonyl or        arylalkylaminocarbonyl optionally substituted with halo, cyano,        or haloalkyl; and    -   n is 1 or 2.

Another aspect is a compound of the formulae herein, wherein:

-   -   R₁ is fluoro;    -   R₂ is fluoro;    -   R₄ is 2,4-difluorophenyl;    -   R₅ is H;    -   Ar₂ is

-   -   MBG is 1-tetrazolyl;    -   R₁₁ is thienyl optionally substituted with 0, 1, 2, or 3        independent R₃;    -   each R₃ is independently —NR₆R₉, haloalkylcarbonyl, alkoxyalkyl,        hydroxyalkyl, acyl, haloalkylthio, —CH(OH)-haloalkyl, alkyl,        alkoxy, cyano, haloalkyl, halo, haloalkoxy, arylalkoxy        optionally substituted with halo, cyano, haloalkyl, or        haloalkoxy, haloalkylaminocarbonyl, arylalkylaminocarbonyl        optionally substituted with halo, cyano, haloalkoxy, or        haloalkyl; and    -   n is 1 or 2.

Another aspect is a compound of the formulae herein, wherein:

-   -   R₁ is fluoro;    -   R₂ is fluoro;    -   R₄ is 2,4-difluorophenyl; and    -   R₅ is H.

Another aspect is a compound of the formulae herein, wherein:

-   -   each R₃ is independently cyano, haloalkyl, halo, haloalkoxy,        optionally substituted arylalkoxy, haloalkylaminocarbonyl,        optionally substituted arylalkylaminocarbonyl; and    -   n is 1 or 2.

Another aspect is a compound of the formulae herein, wherein:

-   -   each R₃ is independently —NR₆R₉, haloalkylcarbonyl, alkoxyalkyl,        hydroxyalkyl, acyl, haloalkylthio, —CH(OH)-haloalkyl, alkyl,        alkoxy, cyano, haloalkyl, halo, haloalkoxy, arylalkoxy        optionally substituted with halo, cyano, haloalkyl, or        haloalkoxy, haloalkylaminocarbonyl, arylalkylaminocarbonyl        optionally substituted with halo, cyano, haloalkoxy, or        haloalkyl; and    -   n is 1 or 2.

Another aspect is a compound of the formulae herein, wherein:

-   -   each R₃ is independently cyano, haloalkyl, halo, haloalkoxy,        optionally substituted arylalkoxy, haloalkylaminocarbonyl,        optionally substituted arylalkylaminocarbonyl; and    -   n is 1.

Another aspect is a compound of the formulae herein, wherein:

-   -   each R₃ is independently cyano, haloalkyl, halo, haloalkoxy,        optionally substituted arylalkoxy, haloalkylaminocarbonyl,        optionally substituted arylalkylaminocarbonyl; and    -   n is 2.

Another aspect is a compound of the formulae herein, wherein:

-   -   each R₃ is independently hydroxy, amino, —NR₆R₉, —SR₁₀,        —C(O)R₁₀, C(O)NR₆R₇, —CH(OH)-haloalkyl, optionally substituted        alkyl, hydroxyalkyl, alkoxyalkyl, isocyano,        cycloalkylaminocarbonyl, aryloxyalkyl, arylalkylthio,        haloalkylthio, arylalkylsulfonyl, arylalkylsulfinyl, optionally        substituted heteroarylalkoxy, or haloalkylcarbonyl; and    -   n is 1 or 2.

Another aspect is a compound of the formulae herein, wherein:

-   -   each R₃ may be optionally substituted with halo, cyano,        haloalkyl, haloalkoxy, alkylaminocarbonyl, heteroaryl, or aryl.

Another aspect is a compound of the formulae herein, wherein:

-   -   each arylalkoxy may be optionally substituted with halo, cyano,        haloalkyl, haloalkoxy, alkylaminocarbonyl, heteroaryl, or aryl.

Another aspect is a compound of the formulae herein, wherein:

-   -   each aryloxyalkyl may be optionally substituted with halo,        cyano, haloalkyl, haloalkoxy, or aryl.

Another aspect is a compound of the formulae herein, wherein:

-   -   each arylalkylthio may be optionally substituted with halo,        haloalkyl, haloalkoxy or cyano.

Another aspect is a compound of the formulae herein, wherein:

-   -   each arylalkylsulfonyl may be optionally substituted with halo,        haloalkyl, haloalkoxy, or cyano.

Another aspect is a compound of the formulae herein, wherein:

-   -   each arylalkylsulfinyl may be optionally substituted with halo,        haloalkyl, haloalkoxy, or cyano.

Another aspect is a compound of the formulae herein, wherein:

-   -   each heteroarylalkoxy may be optionally substituted with halo,        haloalkyl, haloalkoxy, or cyano.

Another aspect is a compound of the formulae herein, wherein:

-   -   each arylthioalkyl may be optionally substituted with halo,        haloalkyl, haloalkoxy, or cyano.

Another aspect is a compound of the formulae herein, wherein:

-   -   each thienyl may be optionally substituted with halo, haloalkyl,        alkyl, haloalkylcarbonyl, haloalkylaminocarbonyl,        haloarylalkylaminocarbonyl, cyanoarylalkylaminocarbonyl,        haloalkylarylalkylaminocarbonyl, heterocycloalkylcarbonyl,        methylsulfonyl-phenylalkylaminocarbonyl, or cyano.

Another aspect is a compound of the formulae herein, wherein:

-   -   each pyridyl within the definition of R₁₁ may be optionally        substituted with halo, cyano, haloalkoxy, or haloalkyl.

Another aspect is a compound of the formulae herein, wherein:

-   -   each indolyl may be optionally substituted with halo, cyano,        haloalkoxy, or haloalkyl.

Another aspect is a compound of the formulae herein, wherein:

-   -   each benzofuranyl may be optionally substituted with halo,        cyano, haloalkoxy, or haloalkyl.

Another aspect is a compound of the formulae herein, wherein:

-   -   each MBG may be optionally substituted with halo, cyano,        haloalkoxy, or haloalkyl.

Another aspect is a compound of the formulae herein, wherein:

-   -   each R₁₁ may be optionally substituted with halo, cyano, alkyl,        haloalkoxy, or haloalkyl.

Another aspect is a compound of the formulae herein, wherein:

-   -   each R₃ is independently 4-cyano, 4-trifluoromethyl, 3-cyano,        4-isopropoxy, 4-fluoro, 3-trifluoromethoxy, 4-trifluoromethoxy,        3-chloro, 4-chloro, 2-fluoro, 5-fluoro,        4-(2,2,2-trifluoroethoxy), 4-(3,3,3-trifluoro,        2,2-difluoropropoxy), 4-cyano-3-fluorophenylmethoxy,        4-cyanophenylmethoxy, 1-hydroxy-2,2,2-trifluoroethyl, or        (4-fluorophenylmethyl)NHC(O)—, 2,4-di-fluoro, 1-methyl,        3,4-di-fluoro, 2-fluoro-4-trifluoromethyl, 3-fluoro,        4-difluoromethyl, 2-fluoro-4-methyl, 5-chloro,        5-trifluoromethyl, 3,5-di-fluoro, 2-fluoro-5-methoxy,        2,6-di-fluoro, 5-methyl, 4-(1,1-difluoroethane),        4-difluoromethoxy, 4-trifluoromethylthio, 3-fluoro-4-chloro,        4-acetyl, 4-hydroxymethyl, 4-methoxymethyl, 5-bromo,        5-difluoromethyl, 5-trifluoroacetyl, 1-(2,2,2-trifluoroethyl),        2-fluoro-4-(methylamino), 4-dimethylamino,        3-fluoro-4-difluoromethyl, 1-difluoromethyl, 2,5-difluoro,        4-formylamino, 4-isocyano, 2-fluoro-4-cyano, 3-fluoro-4-cyano,        2-fluoro-5-cyano, 5-(2,2,2-trifluoroethyl),        4-trifluoroacetylamino, 4-(2,2,2-trifluoroethyl)amino,        4-aminocarbonyl, 2-fluoro-4-amino, 4-acetylamino,        4-(fluorophenyl)methylamino, 4-(2,2,2-trifluoroethyl),        (2,2,2-trifluoroethyl)aminocarbonyl, pyrrolidinylcarbonyl,        4-(fluorophenyl)methyloxy, 4-(fluorophenyl)carbonyl,        1-trifluoroacetyl, 3-(2,2,2-trifluoroethyl)oxy,        3-(cyanophenyl)methyloxy, 4-(trifluoromethoxyphenyl)methyloxy,        [(2-fluoro-4-cyano)phenyl]methyloxy,        [(2-fluoro-5-cyano)phenyl]methyloxy,        3-(trifluoromethoxy)methyloxy, 2,4-(di-fluorophenyl)methyloxy,        3,4-(di-fluorophenyl)methyloxy, 4-(chlorophenyl)methyloxy,        (2-fluoro-4-chlorophenyl)methyloxy,        [4-(methylaminocarbonyl)phenyl]methyloxy,        (5-cyano-2-pyridyl)methyloxy, (2-thiazole)methyloxy,        (3-cyano-4-fluorophenyl)methyloxy,        (2,3-di-fluorophenyl)methyloxy, 2-fluoro-4-chloro,        (3-cyanophenyl)methylaminocarbonyl,        (4-cyanophenyl)methylaminocarbonyl,        (4-trifluoromethylphenyl)methylaminocarbonyl,        (1-morpholino)carbonyl,        [4-(methanesulfonyl)phenyl]methylaminocarbonyl,        (2-fluoro-4-cyanophenyl)methyloxy,        (3-fluoro-5-cyanophenyl)methyloxy, (4-fluorophenyl)sulfonyl,        1-hydroxy-(2,2,3,3,3-pentafluoro)propyl,        (3-fluoro-4-cyanophenyl)methylsulfinyl,        (3-fluoro-4-cyanophenyl)methylthio,        (3-fluoro-4-cyanophenyl)methylsulfonyl,        (2-cyano-5-pyridyl)methyloxy, (3-fluoro-4-cyanophenyl)methyloxy,        1-hydroxyethyl, 2-fluoro-4-methoxy, 4-methylamino, 4-hydroxy,        (4-fluorophenyl)methylamino,        (3-fluorophenyl)methylaminocarbonyl,        (4-fluorophenyl)methylaminocarbonyl,        (2-fluoro-3-cyanophenyl)methyloxy, (4-cyanophenyl)methylthio,        (3-fluoro-4-chlorophenyl)methyloxy, (4-biphenyl)methyloxy,        (4-methylphenyl)methyloxy, (4-ethylphenyl)methyloxy,        (4-difluoromethylphenyl)methyloxy,        (4-trifluoromethylphenyl)methyloxy, 3-cyano-4-fluoro,        (4-(1-pyrrolyl)phenyl)methyloxy, 4-phenyl,        (4-(2-oxazolyl)phenyl)methyloxy, 4-(5-cyanothienyl)methyloxy.

Another aspect is a compound of formula (II), or salt, solvate, hydrateor prodrug thereof, wherein:

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, and R₁₀ are defined as described inthe above embodiments;

Ar is aryl or heteroaryl;

n is 0, 1, 2 or 3.

In one aspect, the compound of any of the formulae herein (e.g., formulaI or formula II) is that wherein the compound inhibits (or is identifiedto inhibit) lanosterol demethylase (CYP51).

In one aspect, the compound of any of the formulae herein (e.g., formulaI or formula II) is that wherein the compound is identified as having anactivity range against a target enzyme (e.g., C. albicans MIC <1.0 μg/mLand A. fumigatus MIC≤64 μg/mL).

The compounds herein include those wherein the compound is identified asattaining affinity, at least in part, for a metalloenzyme by formationof one or more of the following types of chemical interactions or bondsto a metal: sigma bonds, covalent bonds, coordinate-covalent bonds,ionic bonds, pi bonds, delta bonds, or backbonding interactions. Thecompounds can also attain affinity through weaker interactions with themetal such as van der Waals interactions, pi cation interactions,pi-anion interactions, dipole-dipole interactions, ion-dipoleinteractions. In one aspect, the compound is identified as having abonding interaction with the metal via the 1-tetrazolyl moiety; inanother aspect, the compound is identified as having a bondinginteraction with the metal via the N2 of the 1-tetrazolyl moiety; inanother aspect, the compound is identified as having a bondinginteraction with the metal via the N3 of the 1-tetrazolyl moiety; inanother aspect, the compound is identified as having a bondinginteraction with the metal via the N4 of the 1-tetrazolyl moiety. In oneaspect, the compound is identified as having a bonding interaction withthe metal via the 2-tetrazolyl moiety; in another aspect, the compoundis identified as having a bonding interaction with the metal via the N1of the 2-tetrazolyl moiety; in another aspect, the compound isidentified as having a bonding interaction with the metal via the N3 ofthe 2-tetrazolyl moiety; in another aspect, the compound is identifiedas having a bonding interaction with the metal via the N4 of the2-tetrazolyl moiety.

Methods for assessing metal-ligand binding interactions are known in theart as exemplified in references including, for example, “Principles ofBioinorganic Chemistry” by Lippard and Berg, University Science Books,(1994); “Mechanisms of Inorganic Reactions” by Basolo and Pearson JohnWiley & Sons Inc; 2nd edition (September 1967); “Biological InorganicChemistry” by Ivano Bertini, Harry Gray, Ed Stiefel, Joan Valentine,University Science Books (2007); Xue et al. “Nature Chemical Biology”,vol. 4, no. 2, 107-109 (2008).

In certain instances, the compounds of the invention are selected fromthe following of any of the formulae herein (e.g., formula I or formulaII) (and pharmaceutically acceptable salts, solvates, or hydratesthereof)

-   2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(phenylethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (1);-   1-(5-((4-Chlorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (2);-   2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (3);-   2-(2,4-Difluorophenyl)-1-(5-((2,4-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (4);-   2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(trifluoromethyl)phenyl)    ethynyl)pyridin-2-yl)propan-2-ol (5);-   5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)    ethynyl)-N-(4-fluorobenzyl)thiophene-2-carboxamide (6);-   4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)    propyl) pyridin-3-yl) ethynyl) phenoxy) methyl)-2-fluorobenzonitrile    (7);-   4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)benzonitrile    (8);-   2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(2,2,2-trifluoro-1-hydroxyethyl)    phenyl) ethynyl) pyridin-2-yl)propan-2-ol (9);-   2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((1-methyl-1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (10);-   2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)thiophen-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (11);-   2-(2,4-Difluorophenyl)-1-(6-((3,4-difluorophenyl)ethynyl)pyridazin-3-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (12);-   4-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)but-3-yn-2-ol    (13);-   2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoro-1-hydroxyethyl)thiophen-2-yl)ethynyl)pyridin-2-yl)propan-2-ol    (14);-   2-(2,4-difluorophenyl)-1-(5-((3,4-difluorophenyl)ethynyl)pyrazin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (15);-   2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoro-1-hydroxy    ethyl)furan-2-yl)ethynyl)pyridin-2-yl)propan-2-ol (16);-   2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-(3-fluorophenyl)prop-1-yn-1-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (17);-   2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-(4-fluorophenoxy)prop-1-yn-1-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (18);-   2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((1-(4-fluorophenyl)piperidin-4-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (19);-   1-(5-((4-((4-Cyanobenzyl)oxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)    propan-2-yl dihydrogen phosphate (20);-   1-(5-((3-chlorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (21);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-(trifluoromethyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (22);-   2-(2,4-difluorophenyl)-1-(5-(3,3-difluoroprop-1-ynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (23);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (24);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (25);-   1-(5-((4-(difluoromethyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (26);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-methylphenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (27);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((3-fluoropyridin-2-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (28);-   1-(5-((5-chlorothiophen-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (29);-   2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(trifluoromethyl)thiophen-2-yl)ethynyl)pyridin-2-yl)propan-2-ol    (30);-   2-(2,4-difluorophenyl)-1-(5-((3,5-difluoropyridin-2-yl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (31);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((5-fluoropyridin-2-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (32);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((6-fluoropyridin-3-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (33);-   2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(trifluoromethoxy)phenyl)ethynyl)pyridin-2-yl)propan-2-ol    (34);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-methoxyphenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (35);-   2-(2,4-difluorophenyl)-1-(5-((2,6-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (36);-   2-(2,4-difluorophenyl)-1-(5-((3,4-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (37);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((5-methylthiophen-2-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (38);-   1-(5-((4-(1,1-difluoroethyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (39);-   1-(5-((4-(difluoromethoxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (40);-   2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(trifluoromethylthio)phenyl)ethynyl)pyridin-2-yl)propan-2-ol    (41);-   1-(5-((4-chloro-3-fluorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (42);-   2-(4-chloro-2-fluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (43);-   1,1-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (44);-   2-(2,5-difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (45);-   2-(3,4-difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (46);-   1-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenyl)ethanone    (47);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(6-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (48);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(6-((4-fluorophenyl)ethynyl)pyridazin-3-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (49);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(hydroxymethyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (50);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(methoxymethyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (51);-   4-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)-1,1,1-trifluorobut-3-yn-2-ol    (52);-   1-(5-((5-bromothiophen-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (53);-   1-(5-((5-(difluoromethyl)thiophen-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (54);-   1-(5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)thiophen-2-yl)-2,2,2-trifluoroethanone    (55);-   2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((1-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)propan-2-ol    (56);-   2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(3-(2,2,2-trifluoroethoxy)prop-1-ynyl)pyridin-2-yl)propan-2-ol    (57);-   2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(thiophen-2-ylethynyl)pyridin-2-yl)propan-2-ol    (58);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-(methylamino)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (59);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(methylamino)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (60);-   2-(2,4-difluorophenyl)-1-(5-((3,4-difluorophenyl)ethynyl)thiophen-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (61);-   2-(2,4-difluorophenyl)-1-(5-((4-(dimethylamino)phenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (62);-   1-(5-((1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (63);-   1-(5-((4-(difluoromethyl)-3-fluorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (64);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(3-(3-fluorophenyl)prop-1-ynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (65);-   1-(5-((1-(difluoromethyl)-1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (66);-   2-(2,4-difluorophenyl)-1-(5-((2,5-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (67);-   N-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenyl)formamide    (68);-   4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzonitrile    (69);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-isocyanophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (70);-   3-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzonitrile    (71);-   1-(5-((5-bromofuran-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (72);-   4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-3-fluorobenzonitrile    (73);-   4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-2-fluorobenzonitrile    (74);-   3-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-4-fluorobenzonitrile    (75);-   1-(5-((5-(difluoromethyl)furan-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (76);-   2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoroethyl)thiophen-2-yl)ethynyl)pyridin-2-yl)propan-2-ol    (77);-   1-(5-((4-aminophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (78);-   N-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenyl)-2,2,2-trifluoroacetamide    (79);-   2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(2,2,2-trifluoroethylamino)phenyl)ethynyl)pyridin-2-yl)propan-2-ol    (80);-   4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenol    (81);-   4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzamide    (82);-   1-(5-((4-amino-2-fluorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (83);-   N-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenyl)acetamide    (84);-   1-(5-(3-(2,4-difluorophenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (85);-   4-(3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)prop-2-ynyloxy)benzonitrile    (86);-   1-(5-((1H-indol-5-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (87);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-fluorobenzylamino)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (88);-   1-(5-(benzofuran-5-ylethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (89);-   2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(2,2,2-trifluoroethyl)phenyl)ethynyl)pyridin-2-yl)propan-2-ol    (90);-   4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N-(2,2,2-trifluoroethyl)benzamide    (91);-   (4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenyl)(pyrrolidin-1-yl)methanone    (92);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-fluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (93);-   5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide    (94);-   (4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)piperidin-1-yl)(4-fluorophenyl)methanone    (95);-   1-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)piperidin-1-yl)-2,2,2-trifluoroethanone    (96);-   2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((3-(2,2,2-trifluoroethoxy)phenyl)ethynyl)pyridin-2-yl)propan-2-ol    (97);-   3-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N-(2,2,2-trifluoroethyl)benzamide    (98);-   1,1-difluoro-2-(4-fluorophenyl)-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (99);-   3-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)benzonitrile    (100);-   2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(4-(trifluoromethoxy)benzyloxy)phenyl)ethynyl)pyridin-2-yl)propan-2-ol    (101);-   4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-3-fluorobenzonitrile    (102);-   3-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-4-fluorobenzonitrile    (103);-   2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(3-(trifluoromethoxy)benzyloxy)phenyl)ethynyl)pyridin-2-yl)propan-2-ol    (104);-   1-(5-((4-(2,4-difluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (105);-   1-(5-((4-(3,4-difluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (106);-   1-(5-((4-(4-chlorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (107);-   1-(5-((4-(4-chloro-2-fluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (108);-   4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-N-methylbenzamide    (109);-   6-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)nicotinonitrile    (110);-   2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(thiazol-2-ylmethoxy)phenyl)ethynyl)pyridin-2-yl)propan-2-ol    (111);-   5-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-2-fluorobenzonitrile    (112);-   1-(5-((4-(2,3-difluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (113);-   1-(5-(3-(4-chlorophenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (114);-   4-(3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)prop-2-ynyloxy)-3-fluorobenzonitrile    (115);-   4-(3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)prop-2-ynyloxy)-2-fluorobenzonitrile    (116);-   1-(5-(3-(4-chloro-2-fluorophenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (117);-   1-(5-(3-(4-(difluoromethyl)phenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (118);-   5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N-(3-fluorobenzyl)thiophene-2-carboxamide    (119);-   N-(3-cyanobenzyl)-5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)thiophene-2-carboxamide    (120);-   N-(4-cyanobenzyl)-5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)thiophene-2-carboxamide    (121);-   5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N-(4-(trifluoromethyl)benzyl)thiophene-2-carboxamide    (122);-   (5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)thiophen-2-yl)(morpholino)methanone    (123);-   (5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)thiophen-2-yl)(pyrrolidin-1-yl)methanone    (124);-   5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N-(4-(methylsulfonyl)benzyl)thiophene-2-carboxamide    (125);-   3-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-2-fluorobenzonitrile    (126);-   3-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-5-fluorobenzonitrile    (127);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(piperidin-4-ylethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (128);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((1-(4-fluorophenylsulfonyl)piperidin-4-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (129);-   1-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenyl)-2,2,3,3,3-pentafluoropropan-1-ol    (130);-   4-((4-((6-(2-(2,5-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-2-fluorobenzonitrile    (131);-   4-((4-((6-(2-(4-chloro-2-fluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-2-fluorobenzonitrile    (132);-   4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenylthio)methyl)-2-fluorobenzonitrile    (133);-   4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenylsulfinyl)methyl)-2-fluorobenzonitrile    (134);-   4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenylsulfonyl)methyl)-2-fluorobenzonitrile    (135);-   4-((4-((6-(2-(2,5-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)benzonitrile    (136);-   4-((4-((6-(2-(4-chloro-2-fluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)benzonitrile    (137);-   4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenylthio)methyl)benzonitrile    (138);-   5-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)picolinonitrile    (139);-   1-(5-((4-(4-cyanobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-yl    dihydrogen phosphate (140);-   5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl)ethynyl)-N-(4-fluorobenzyl)thiophene-2-carboxamide    (141);-   4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)benzonitrile    (142);-   4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-2-fluorobenzonitrile    (143);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-yl    2-aminoacetate hydrochloride (144);-   (2S)-2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-yl    2,6-diaminohexanoate dihydrochloride (145);-   1-(5-((4-(4-chloro-3-fluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (146);-   1-(5-((4-(biphenyl-4-ylmethoxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (147);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-methylbenzyloxy)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (148);-   2-(2,4-difluorophenyl)-1-(5-((4-(4-ethylbenzyloxy)phenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (149);-   1-(5-((4-(4-(difluoromethyl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (150);-   (+)-1-(5-((4-(4-(difluoromethyl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    ((+)-150);-   2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(4-(trifluoromethyl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)propan-2-ol    (151);-   4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzyloxy)-3-fluorobenzonitrile    (152);-   5-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzyloxy)-2-fluorobenzonitrile    (153);-   1-(5-((4-(4-(1H-pyrazol-1-yl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (154);-   4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzyloxy)benzonitrile    (155);-   1-(5-((4-((4-chlorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (156);-   1-(5-((4-((biphenyl-4-yloxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (157);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-(oxazol-2-yl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (158);-   2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-((4-fluorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol    (159);-   1-(5-((4-((3,4-difluorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (160);-   1-(5-((4-((4-(difluoromethyl)phenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (161);-   4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzylthio)benzonitrile    (162);-   5-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)thiophene-2-carbonitrile    (163);-   4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzyloxy)-2-fluorobenzonitrile    (164);-   1-(5-((4-((4-chloro-3-fluorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol    (165);-   4-((3-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)benzonitrile    (166).

In another aspect, the invention provides a pharmaceutical compositioncomprising the compound of any of the formulae herein (e.g., formula Ior formula II) and a pharmaceutically acceptable carrier.

In other aspects, the invention provides a method of modulatingmetalloenzyme activity in a subject, comprising contacting the subjectwith a compound of any of the formulae herein (e.g., formula I orformula II), in an amount and under conditions sufficient to modulatemetalloenzyme activity.

In another aspect, the invention provides a method of treating a subjectsuffering from or susceptible to a disorder or disease, wherein thesubject has been identified as in need of treatment for the disorder ordisease, comprising administering to said subject in need thereof, aneffective amount of a compound or pharmaceutical composition of any ofthe formulae herein (e.g., formula I or formula II), such that saidsubject is treated for said disorder.

In another aspect the subject is an animal other than a human

The methods herein include those wherein the disorder or disease isassociated with one or more of the following pathogenic fungi: Absidiacorymbifera, Ajellomyces dermatitidis, Arthroderma benhamiae,Arthroderma fulvum, Arthroderma gypseum, Arthroderma incurvaturn,Arthroderma otae, Arthroderma vanbreuseghemii, Aspergillus flavus,Aspergillus fumigates, Aspergillus niger, Blastomyces dermatitidis,Candida albicans, Candida glabrata, Candida guilliermondii, Candidakrusei, Candida parapsilosis, Candida tropicalis, Candida pelliculosa,Cladophialophora carrionii, Coccidioides immitis, Cryptococcusneoformans, Cunninghamella sp., Epidermophyton floccosum, Exophialadermatitidis, Filobasidiella neoformans, Fonsecaea pedrosoi, Fusariumsolani, Geotrichum candidum, Histoplasma capsulaturn, Hortaea werneckii,Issatschenkia orientalis, Madurella grisae, Malassezia fur fur,Malassezia globosa, Malassezia obtusa, Malassezia pachydermatis,Malassezia restricta, Malassezia slooffiae, Malassezia sympodialis,Microsporum canis, Microsporum fulvum, Microsporum gypseum, Mucorcircinelloides, Nectria haematococca, Paecilomyces variotii,Paracoccidioides brasiliensis, Penicillium marneffei, Pichia anomala,Pichia guilliermondii, Pneumocystis carinii, Pseudallescheria boydii,Rhizopus oryzae, Rhodotorula rubra, Scedosporium apiospernium,Schizophyllum commune, Sporothrix schenckii, Trichophytonmentagrophytes, Trichophyton rubrum, Trichophyton verrucosum,Trichophyton violaceum, Trichosporon asahii, Trichosporon cutaneum,Trichosporon inkin, Trichosporon mucoides.

The methods herein include those wherein the disorder or disease isAspergillosis, Blastomycosis, Candidiasis, Chromomycosis,Coccidioidomycosis, Cryptococcosis, Dermatophytoses, Histoplasmosis,Keratomycosis, Lobomycosis, Malassezia infection, Mucormycosis,Paracoccidioidomycosis, Penicillium marneffei infection,Phaeohyphomycosis, Pneumocyctis pneumonia, or Rhinosporidiosis.

The methods herein include those wherein the disorder or disease isChagas disease (Genus Trypanosoma), African trypanosomiasis (GenusTrypanosoma), leishmaniasis (Genus Leishmania), tuberculosis (GenusMycobacterium), leprosy (Genus Mycobacterium), malaria (GenusPlasmodium), or tinea (capitis, corporis, pedis, tonsurans, versicolor).

In one aspect, the invention provides a method of treating a subjectsuffering from or susceptible to a metalloenzyme-related disorder ordisease, comprising administering to the subject an effective amount ofa compound or pharmaceutical composition of any of the formulae herein(e.g., formula I or formula II).

In another aspect, the invention provides a method of treating a subjectsuffering from or susceptible to a metalloenzyme-related disorder ordisease, wherein the subject has been identified as in need of treatmentfor a metalloenzyme-related disorder or disease, comprisingadministering to said subject in need thereof, an effective amount of acompound or pharmaceutical composition of any of the formulae herein(e.g., formula I or formula II), such that said subject is treated forsaid disorder.

In another aspect, the invention provides a method of treating a subjectsuffering from or susceptible to a metalloenzyme-mediated disorder ordisease, wherein the subject has been identified as in need of treatmentfor a metalloenzyme-mediated disorder or disease, comprisingadministering to said subject in need thereof, an effective amount of acompound or pharmaceutical composition of any of the formulae herein(e.g., formula I or formula II), such that metalloenzyme activity insaid subject is modulated (e.g., down regulated, inhibited).

The methods herein include those wherein the disease or disorder ismediated by any of 4-hydroxyphenyl pyruvate dioxygenase, 5-lipoxygenase,adenosine deaminase, alcohol dehydrogenase, aminopeptidase N,angiotensin converting enzyme, aromatase (CYP19), calcineurin, carbamoylphosphate synthetase, carbonic anhydrase family, catechol o-methyltransferase, cyclooxygenase family, dihydropyrimidine dehydrogenase-1,DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase,fumarate reductase, GABA aminotransferase, HIF-prolyl hydroxylase,histone deacetylase family, HIV integrase, HIV-1 reverse transcriptase,isoleucine tRNA ligase, lanosterol demethylase (CYP51), matrixmetalloprotease family, methionine aminopeptidase, neutralendopeptidase, nitric oxide synthase family, phosphodiesterase III,phosphodiesterase IV, phosphodiesterase V, pyruvate ferredoxinoxidoreductase, renal peptidase, ribonucleoside diphosphate reductase,thromboxane synthase (CYP5a), thyroid peroxidase, tyrosinase, urease, orxanthine oxidase.

The methods herein include those wherein the disease or disorder ismediated by any of 1-deoxy-d-xylulose-5-phosphate reductoisomerase(DXR), 17-alpha hydroxylase (CYP17), aldosterone synthase (CYP11B2),aminopeptidase P, anthrax lethal factor, arginase, beta-lactamase,cytochrome P450 2A6, d-ala d-ala ligase, dopamine beta-hydroxylase,endothelin converting enzyme-1, glutamate carboxypeptidase II,glutaminyl cyclase, glyoxalase, heme oxygenase, HPV/HSV E1 helicase,indoleamine 2,3-dioxygenase, leukotriene A4 hydrolase, methionineaminopeptidase 2, peptide deformylase, phosphodiesterase VII, relaxase,retinoic acid hydroxylase (CYP26), TNF-alpha converting enzyme (TACE),UDP-(3-O—(R-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase (LpxC),vascular adhesion protein-1 (VAP-1), or vitamin D hydroxylase (CYP24).

The methods herein include those wherein the disease or disorder iscancer, cardiovascular disease, inflammatory disease, infectiousdisease, metabolic disease, ophthalmologic disease, central nervoussystem (CNS) disease, urologic disease, or gastrointestinal disease.

The methods herein include those wherein the disease or disorder isprostate cancer, breast cancer, inflammatory bowel disease, psoriasis,systemic fungal infection, skin structure fungal infection, mucosalfungal infection, or onychomycosis.

Methods delineated herein include those wherein the subject isidentified as in need of a particular stated treatment. Identifying asubject in need of such treatment can be in the judgment of a subject ora health care professional and can be subjective (e.g. opinion) orobjective (e.g. measurable by a test or diagnostic method).

Another aspect of the invention is a composition comprising a compoundof a formulae herein (e.g., formula (I) or formula (II)) and anagriculturally acceptable carrier.

Another aspect of the invention is a method of treating or preventing ametalloenzyme-mediated disease or disorder in or on a plant comprisingcontacting a compound herein with the plant.

Another aspect of the invention is a method of inhibiting metalloenzymeactivity in or on a plant comprising contacting a compound herein withthe plant.

DETAILED DESCRIPTION Definitions

In order that the invention may be more readily understood, certainterms are first defined here for convenience.

As used herein, the term “treating” a disorder encompasses preventing,ameliorating, mitigating and/or managing the disorder and/or conditionsthat may cause the disorder. The terms “treating” and “treatment” referto a method of alleviating or abating a disease and/or its attendantsymptoms. In accordance with the present invention “treating” includespreventing, blocking, inhibiting, attenuating, protecting against,modulating, reversing the effects of and reducing the occurrence ofe.g., the harmful effects of a disorder.

As used herein, “inhibiting” encompasses preventing, reducing andhalting progression. Note that “enzyme inhibition” (e.g., metalloenzymeinhibition) is distinguished and described below.

The term “modulate” refers to increases or decreases in the activity ofan enzyme in response to exposure to a compound of the invention.

The terms “isolated,” “purified,” or “biologically pure” refer tomaterial that is substantially or essentially free from components thatnormally accompany it as found in its native state. Purity andhomogeneity are typically determined using analytical chemistrytechniques such as polyacrylamide gel electrophoresis or highperformance liquid chromatography. Particularly, in embodiments thecompound is at least 85% pure, more preferably at least 90% pure, morepreferably at least 95% pure, and most preferably at least 99% pure.

The term “administration” or “administering” includes routes ofintroducing the compound(s) to a subject to perform their intendedfunction. Examples of routes of administration which can be used includeinjection (subcutaneous, intravenous, parenterally, intraperitoneally,intrathecal), topical, oral, inhalation, rectal and transdermal.

The term “effective amount” includes an amount effective, at dosages andfor periods of time necessary, to achieve the desired result. Aneffective amount of compound may vary according to factors such as thedisease state, age, and weight of the subject, and the ability of thecompound to elicit a desired response in the subject. Dosage regimensmay be adjusted to provide the optimum therapeutic response. Aneffective amount is also one in which any toxic or detrimental effects(e.g., side effects) of the inhibitor compound are outweighed by thetherapeutically beneficial effects.

The phrases “systemic administration,” “administered systemically”,“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound(s), drug or other material,such that it enters the patient's system and, thus, is subject tometabolism and other like processes.

The term “therapeutically effective amount” refers to that amount of thecompound being administered sufficient to prevent development of oralleviate to some extent one or more of the symptoms of the condition ordisorder being treated.

A therapeutically effective amount of compound (i.e., an effectivedosage) may range from about 0.005 μg/kg to about 200 mg/kg, preferablyabout 0.01 mg/kg to about 200 mg/kg, more preferably about 0.015 mg/kgto about 30 mg/kg of body weight. In other embodiments, thetherapeutically effect amount may range from about 1.0 pM to about 10μM. The skilled artisan will appreciate that certain factors mayinfluence the dosage required to effectively treat a subject, includingbut not limited to the severity of the disease or disorder, previoustreatments, the general health and/or age of the subject, and otherdiseases present. Moreover, treatment of a subject with atherapeutically effective amount of a compound can include a singletreatment or, preferably, can include a series of treatments. In oneexample, a subject is treated with a compound in the range of betweenabout 0.005 μg/kg to about 200 mg/kg of body weight, one time per dayfor between about 1 to 10 weeks, preferably between 2 to 8 weeks, morepreferably between about 3 to 7 weeks, and even more preferably forabout 4, 5, or 6 weeks. In another example, a subject may be treateddaily for several years in the setting of a chronic condition orillness. It will also be appreciated that the effective dosage of acompound used for treatment may increase or decrease over the course ofa particular treatment.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “diastereomers” refers to stereoisomers with two or morecenters of dissymmetry and whose molecules are not mirror images of oneanother.

The term “enantiomers” refers to two stereoisomers of a compound whichare non-superimposable mirror images of one another. An equimolarmixture of two enantiomers is called a “racemic mixture” or a“racemate.”

The term “isomers” or “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space.

The term “prodrug” includes compounds with moieties which can bemetabolized in vivo. Generally, the prodrugs are metabolized in vivo byesterases or by other mechanisms to active drugs. Examples of prodrugsand their uses are well known in the art (See, e.g., Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19). The prodrugs can beprepared in situ during the final isolation and purification of thecompounds, or by separately reacting the purified compound in its freeacid form or hydroxyl with a suitable esterifying agent. Hydroxyl groupscan be converted into esters via treatment with a carboxylic acid.Examples of prodrug moieties include substituted and unsubstituted,branched or unbranched lower alkyl ester moieties, (e.g., propionoicacid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkylesters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters(e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g.,pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkylesters (e.g., benzyl ester), substituted (e.g., with methyl, halo, ormethoxy substituents) aryl and aryl-lower alkyl esters, amides,lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Preferredprodrug moieties are propionoic acid esters and acyl esters. Prodrugswhich are converted to active forms through other mechanisms in vivo arealso included. In aspects, the compounds of the invention are prodrugsof any of the formulae herein.

The term “subject” refers to animals such as mammals, including, but notlimited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,cats, rabbits, rats, mice and the like. In certain embodiments, thesubject is a human.

The terms “a,” “an,” and “the” refer to “one or more” when used in thisapplication, including the claims. Thus, for example, reference to “asample” includes a plurality of samples, unless the context clearly isto the contrary (e.g., a plurality of samples), and so forth.

Throughout this specification and the claims, the words “comprise,”“comprises,” and “comprising” are used in a non-exclusive sense, exceptwhere the context requires otherwise.

As used herein, the term “about,” when referring to a value is meant toencompass variations of, in some embodiments ±20%, in some embodiments±10%, in some embodiments ±5%, in some embodiments ±1%, in someembodiments ±0.5%, and in some embodiments ±0.1% from the specifiedamount, as such variations are appropriate to perform the disclosedmethods or employ the disclosed compositions.

Use of the word “inhibitor” herein is meant to mean a molecule thatexhibits activity for inhibiting a metalloenzyme. By “inhibit” herein ismeant to decrease the activity of metalloenzyme, as compared to theactivity of metalloenzyme in the absence of the inhibitor. In someembodiments, the term “inhibit” means a decrease in metalloenzymeactivity of at least about 5%, at least about 10%, at least about 20%,at least about 25%, at least about 50%, at least about 60%, at leastabout 70%, at least about 80%, at least about 90%, or at least about95%. In other embodiments, inhibit means a decrease in metalloenzymeactivity of about 5% to about 25%, about 25% to about 50%, about 50% toabout 75%, or about 75% to 100%. In some embodiments, inhibit means adecrease in metalloenzyme activity of about 95% to 100%, e.g., adecrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such decreasescan be measured using a variety of techniques that would be recognizableby one of skill in the art. Particular assays for measuring individualactivity are described below.

Furthermore the compounds of the invention include olefins having eithergeometry: “Z” refers to what is referred to as a “cis” (same side)configuration whereas “E” refers to what is referred to as a “trans”(opposite side) configuration. With respect to the nomenclature of achiral center, the terms “d” and “1” configuration are as defined by theIUPAC Recommendations. As to the use of the terms, diastereomer,racemate, epimer and enantiomer, these will be used in their normalcontext to describe the stereochemistry of preparations.

As used herein, the term “alkyl” refers to a straight-chained orbranched hydrocarbon group containing 1 to 12 carbon atoms. The term“lower alkyl” refers to a C1-C6 alkyl chain. Examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl.Alkyl groups may be optionally substituted with one or moresubstituents.

The term “haloalkyl” refers to an alkyl group that is substituted by oneor more halo substituents. Examples of haloalkyl groups includefluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl,chloromethyl, and 2,2,2-trifluoroethyl.

The term “alkenyl” refers to an unsaturated hydrocarbon chain that maybe a straight chain or branched chain, containing 2 to 12 carbon atomsand at least one carbon-carbon double bond. Alkenyl groups may beoptionally substituted with one or more substituents.

The term “arylalkenyl” refers to an unsaturated hydrocarbon chain thatmay be a straight chain or branched chain, containing 2 to 12 carbonatoms and at least one carbon-carbon double bond wherein one or more ofthe sp² hybridized carbons of the alkenyl unit attaches to an arylmoiety. Alkenyl groups may be optionally substituted with one or moresubstituents.

The term “alkynyl” refers to an unsaturated hydrocarbon chain that maybe a straight chain or branched chain, containing the 2 to 12 carbonatoms and at least one carbon-carbon triple bond. Alkynyl groups may beoptionally substituted with one or more substituents.

The term “arylalkynyl” refers to an unsaturated hydrocarbon chain thatmay be a straight chain or branched chain, containing 2 to 12 carbonatoms and at least one carbon-carbon triple bond wherein one or more ofthe sp hybridized carbons of the alkynyl unit attaches to an arylmoiety. Alkynyl groups may be optionally substituted with one or moresubstituents.

The sp² or sp carbons of an alkenyl group and an alkynyl group,respectively, may optionally be the point of attachment of the alkenylor alkynyl groups.

The term “alkoxy” refers to an —O-alkyl substituent.

As used herein, the term “halogen”, “hal” or “halo” means —F, —Cl, —Bror —I.

The term “alkylthio” refers to an —S-alkyl substituent.

The term “alkoxyalkyl” refers to an -alkyl-O-alkyl substituent.

The term “haloalkoxy” refers to an —O-alkyl that is substituted by oneor more halo substituents. Examples of haloalkoxy groups includetrifluoromethoxy, and 2,2,2-trifluoroethoxy.

The term “haloalkoxyalkyl” refers to an -alkyl-O-alkyl′ where the alkyl′is substituted by one or more halo substituents.

The term “haloalkylaminocarbonyl” refers to a —C(O)-amino-alkyl wherethe alkyl is substituted by one or more halo substituents.

The term “haloalkylthio” refers to an —S-alkyl that is substituted byone or more halo substituents. Examples of haloalkylthio groups includetrifluoromethylthio, and 2,2,2-trifluoroethylthio.

The term “haloalkylcarbonyl” refers to an —C(O)-alkyl that issubstituted by one or more halo substituents. An example of ahaloalkylcarbonyl group includes trifluoroacetyl.

The term “cycloalkyl” refers to a hydrocarbon 3-8 membered monocyclic or7-14 membered bicyclic ring system having at least one saturated ring orhaving at least one non-aromatic ring, wherein the non-aromatic ring mayhave some degree of unsaturation. Cycloalkyl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a cycloalkyl group may be substituted by asubstituent. Representative examples of cycloalkyl group includecyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and thelike.

The term “cycloalkoxy” refers to an —O-cycloalkyl substituent.

The term “cycloalkoxyalkyl” refers to an -alkyl-O-cycloalkylsubstituent.

The term “cycloalkylalkoxy” refers to an —O-alkyl-cycloalkylsubstituent.

The term “cycloalkylaminocarbonyl” refers to an —C(O)—NH-cycloalkylsubstituent.

The term “aryl” refers to a hydrocarbon monocyclic, bicyclic ortricyclic aromatic ring system. Aryl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by asubstituent. Examples of aryl groups include phenyl, naphthyl,anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

The term “aryloxy” refers to an —O-aryl substituent.

The term “arylalkoxy” refers to an —O-alkyl-aryl substituent.

The term “arylalkylthio” refers to an —S-alkyl-aryl substituent.

The term “arylthioalkyl” refers to an -alkyl-S-aryl substituent.

The term “arylalkylaminocarbonyl” refers to a —C(O)-amino-alkyl-arylsubstituent.

The term “arylalkylsulfonyl” refers to an —S(O)₂-alkyl-aryl substituent.

The term “arylalkylsulfinyl” refers to an —S(O)-alkyl-aryl substituent.

The term “aryloxyalkyl” refers to an -alkyl-O-aryl substituent.

The term “alkylaryl” refers to an -aryl-alkyl substituent.

The term “arylalkyl” refers to an -alkyl-aryl substituent.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-4 ring heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andthe remainder ring atoms being carbon (with appropriate hydrogen atomsunless otherwise indicated). Heteroaryl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a heteroaryl group may be substituted by aB substituent. Examples of heteroaryl groups include pyridyl, furanyl,thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl thiazolyl,isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and thelike.

The term “heteroaryloxy” refers to an —O-heteroaryl substituent.

The term “heteroarylalkoxy” refers to an —O-alkyl-heteroarylsubstituent.

The term “heteroaryloxyalkyl” refers to an -alkyl-O-heteroarylsubstituent.

The term “nitrogen-containing heteroaryl” refers to a heteroaryl grouphaving 1-4 ring nitrogen heteroatoms if monocyclic, 1-6 ring nitrogenheteroatoms if bicyclic, or 1-9 ring nitrogen heteroatoms if tricyclic.

The term “heterocycloalkyl” refers to a nonaromatic 3-8 memberedmonocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ringsystem comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, S, B, P or Si, wherein the nonaromatic ring system iscompletely saturated. Heterocycloalkyl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a heterocycloalkyl group may besubstituted by a substituent. Representative heterocycloalkyl groupsinclude piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl,thiirenyl, and the like.

The term “alkylamino” refers to an amino substituent which is furthersubstituted with one or two alkyl groups. The term “aminoalkyl” refersto an alkyl substituent which is further substituted with one or moreamino groups. The term “hydroxyalkyl” or “hydroxylalkyl” refers to analkyl substituent which is further substituted with one or more hydroxylgroups. The alkyl or aryl portion of alkylamino, aminoalkyl,mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl,sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionallysubstituted with one or more substituents.

Acids and bases useful in the methods herein are known in the art. Acidcatalysts are any acidic chemical, which can be inorganic (e.g.,hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic(e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid,ytterbium triflate) in nature. Acids are useful in either catalytic orstoichiometric amounts to facilitate chemical reactions. Bases are anybasic chemical, which can be inorganic (e.g., sodium bicarbonate,potassium hydroxide) or organic (e.g., triethylamine, pyridine) innature. Bases are useful in either catalytic or stoichiometric amountsto facilitate chemical reactions.

Alkylating agents are any reagent that is capable of effecting thealkylation of the functional group at issue (e.g., oxygen atom of analcohol, nitrogen atom of an amino group). Alkylating agents are knownin the art, including in the references cited herein, and include alkylhalides (e.g., methyl iodide, benzyl bromide or chloride), alkylsulfates (e.g., methyl sulfate), or other alkyl group-leaving groupcombinations known in the art. Leaving groups are any stable speciesthat can detach from a molecule during a reaction (e.g., eliminationreaction, substitution reaction) and are known in the art, including inthe references cited herein, and include halides (e.g., I—, Cl—, Br—,F—), hydroxy, alkoxy (e.g., —OMe, —O-t-Bu), acyloxy anions (e.g., —OAc,—OC(O)CF₃), sulfonates (e.g., mesyl, tosyl), acetamides (e.g.,—NHC(O)Me), carbamates (e.g., N(Me)C(O)Ot-Bu), phosphonates (e.g.,—OP(O)(OEt)₂), water or alcohols (protic conditions), and the like.

In certain embodiments, substituents on any group (such as, for example,alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl,cycloalkyl, heterocycloalkyl) can be at any atom of that group, whereinany group that can be substituted (such as, for example, alkyl, alkenyl,alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl,heterocycloalkyl) can be optionally substituted with one or moresubstituents (which may be the same or different), each replacing ahydrogen atom. Examples of suitable substituents include, but are notlimited to alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano,nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl),carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl,thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl,dialkylamino, alkylcarbonylamino, alkylaminocarbonyl,alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl,or arylamino-substituted aryl; arylalkylamino, aralkylaminocarbonyl,amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, arylsulfonylamino, imino, carboxamido, carbamido,carbamyl, thioureido, thiocyanato, sulfoamido, sulfonylalkyl,sulfonylaryl, mercaptoalkoxy, N-hydroxyamidinyl, or N′-aryl,N″-hydroxyamidinyl.

Compounds of the invention can be made by means known in the art oforganic synthesis. Methods for optimizing reaction conditions, ifnecessary minimizing competing by-products, are known in the art.Reaction optimization and scale-up may advantageously utilize high-speedparallel synthesis equipment and computer-controlled microreactors (e.g.Design And Optimization in Organic Synthesis, 2^(nd) Edition, Carlson R,Ed, 2005; Elsevier Science Ltd.; Jahnisch, K et al, Angew. Chem. Int.Ed. Engl. 2004 43: 406; and references therein). Additional reactionschemes and protocols may be determined by the skilled artesian by useof commercially available structure-searchable database software, forinstance, SciFinder® (CAS division of the American Chemical Society) andCrossFire Beilstein® (Elsevier MDL), or by appropriate keyword searchingusing an internet search engine such as Google® or keyword databasessuch as the US Patent and Trademark Office text database.

As can be appreciated by the skilled artisan, methods of synthesizingthe compounds of the formulae herein will be evident to those ofordinary skill in the art, including in the schemes and examples herein.Additionally, the various synthetic steps may be performed in analternate sequence or order to give the desired compounds. In addition,the solvents, temperatures, reaction durations, etc. delineated hereinare for purposes of illustration only and one of ordinary skill in theart will recognize that variation of the reaction conditions can producethe desired compounds of the present invention.

The compounds herein may also contain linkages (e.g., carbon-carbonbonds) wherein bond rotation is restricted about that particularlinkage, e.g. restriction resulting from the presence of a ring ordouble bond. Accordingly, all cis/trans and E/Z isomers are expresslyincluded in the present invention. The compounds herein may also berepresented in multiple tautomeric forms, in such instances, theinvention expressly includes all tautomeric forms of the compoundsdescribed herein, even though only a single tautomeric form may berepresented. All such isomeric forms of such compounds herein areexpressly included in the present invention. All crystal forms andpolymorphs of the compounds described herein are expressly included inthe present invention. Also embodied are extracts and fractionscomprising compounds of the invention. The term isomers is intended toinclude diastereoisomers, enantiomers, regioisomers, structural isomers,rotational isomers, tautomers, and the like. For compounds which containone or more stereogenic centers, e.g., chiral compounds, the methods ofthe invention may be carried out with an enantiomerically enrichedcompound, a racemate, or a mixture of diastereomers.

Preferred enantiomerically enriched compounds have an enantiomericexcess of 50% or more, more preferably the compound has an enantiomericexcess of 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more. In preferredembodiments, only one enantiomer or diastereomer of a chiral compound ofthe invention is administered to cells or a subject.

Methods of Treatment

In one aspect, the invention provides a method of treating a subjectsuffering from or susceptible to a disorder or disease, comprisingadministering to the subject an effective amount of a compound orpharmaceutical composition of any of the formulae herein (e.g., formulaI or formula II).

In other aspects, the invention provides a method of treating a subjectsuffering from or susceptible to a disorder or disease, wherein thesubject has been identified as in need of treatment for ametalloenzyme-mediated disorder or disease, comprising administering tosaid subject in need thereof, an effective amount of a compound orpharmaceutical composition of any of the formulae herein (e.g., formulaI or formula II), such that said subject is treated for said disorder.

In one aspect, the invention provides a method of modulating themetalloenzyme activity of a cell in a subject, comprising contacting thesubject with a compound of any of the formulae herein (e.g., formula Ior formula II), in an amount and under conditions sufficient to modulatemetalloenzyme activity.

In one embodiment, the modulation is inhibition.

In another aspect, the invention provides a method of treating a subjectsuffering from or susceptible to a metalloenzyme-mediated disorder ordisease, comprising administering to the subject an effective amount ofa compound or pharmaceutical composition of any of the formulae herein(e.g., formula I or formula II).

In other aspects, the invention provides a method of treating a subjectsuffering from or susceptible to a metalloenzyme-mediated disorder ordisease, wherein the subject has been identified as in need of treatmentfor a metalloenzyme-mediated disorder or disease, comprisingadministering to said subject in need thereof, an effective amount of acompound or pharmaceutical composition of any of the formulae herein(e.g., formula I or formula II), such that said subject is treated forsaid disorder.

In certain embodiments, the invention provides a method of treating adisease, disorder or symptom thereof, wherein the disorder is cancer,cardiovascular disease, inflammatory disease or infectious disease. Inother embodiments the disease, disorder or symptom thereof is metabolicdisease, ophthalmologic disease, central nervous system (CNS) disease,urologic disease, or gastrointestinal disease. In certain embodimentsthe disease is prostate cancer, breast cancer, inflammatory boweldisease, psoriasis, systemic fungal infection, skin structure fungalinfection, mucosal fungal infection, and onychomycosis.

In certain embodiments, the subject is a mammal, preferably a primate orhuman.

In another embodiment, the invention provides a method as describedabove, wherein the effective amount of the compound of any of theformulae herein (e.g., formula I or formula II) is as described above.

In another embodiment, the invention provides a method as describedabove, wherein the compound of any of the formulae herein (e.g., formulaI or formula II) is administered intravenously, intramuscularly,subcutaneously, intracerebroventricularly, orally or topically.

In another embodiment, the invention provides a method as describedherein wherein the compound of any of the formulae herein (e.g., formulaI or formula II) demonstrates selectivity for an activity range againsta target enzyme (e.g., C. albicans MIC <1.0 g/mL and A. fumigatus MIC≤64μg/mL).

In other embodiments, the invention provides a method as describedabove, wherein the compound of any of the formulae herein (e.g., formulaI or formula II) is administered alone or in combination with one ormore other therapeutics. In a further embodiment, the additionaltherapeutic agent is an anti-cancer agent, antifungal agent,cardiovascular agent, anti-inflammatory agent, chemotherapeutic agent,an anti-angiogenesis agent, cytotoxic agent, an anti-B proliferationagent, metabolic disease agent, ophthalmologic disease agent, centralnervous system (CNS) disease agent, urologic disease agent, orgastrointestinal disease agent.

Another object of the present invention is the use of a compound asdescribed herein (e.g., of any formulae herein) in the manufacture of amedicament for use in the treatment of a metalloenzyme-mediated disorderor disease. Another object of the present invention is the use of acompound as described herein (e.g., of any formulae herein) for use inthe treatment of a metalloenzyme-mediated disorder or disease. Anotherobject of the present invention is the use of a compound as describedherein (e.g., of any formulae herein) in the manufacture of anagricultural composition for use in the treatment or prevention of ametalloenzyme-mediated disorder or disease in agricultural or agrariansettings.

Pharmaceutical Compositions

In one aspect, the invention provides a pharmaceutical compositioncomprising the compound of any of the formulae herein (e.g., formula Ior formula II) and a pharmaceutically acceptable carrier.

In another embodiment, the invention provides a pharmaceuticalcomposition further comprising an additional therapeutic agent. In afurther embodiment, the additional therapeutic agent is an anti-canceragent, antifungal agent, cardiovascular agent, anti-inflammatory agent,chemotherapeutic agent, an anti-angiogenesis agent, cytotoxic agent, ananti-proliferation agent, metabolic disease agent, ophthalmologicdisease agent, central nervous system (CNS) disease agent, urologicdisease agent, or gastrointestinal disease agent.

In one aspect, the invention provides a kit comprising an effectiveamount of a compound of any of the formulae herein (e.g., formula I orformula II), in unit dosage form, together with instructions foradministering the compound to a subject suffering from or susceptible toa metalloenzyme-mediated disease or disorder, including cancer, solidtumor, cardiovascular disease, inflammatory disease, infectious disease.In other embodiments the disease, disorder or symptom thereof ismetabolic disease, ophthalmologic disease, central nervous system (CNS)disease, urologic disease, or gastrointestinal disease.

The term “pharmaceutically acceptable salts” or “pharmaceuticallyacceptable carrier” is meant to include salts of the active compoundswhich are prepared with relatively nontoxic acids or bases, depending onthe particular substituents found on the compounds described herein.When compounds of the present invention contain relatively acidicfunctionalities, base addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredbase, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable base addition salts include sodium,potassium, calcium, ammonium, organic amino, or magnesium salt, or asimilar salt. When compounds of the present invention contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like (see, e.g., Berge et al.,Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts. Other pharmaceutically acceptable carriersknown to those of skill in the art are suitable for the presentinvention.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

The invention also provides a pharmaceutical composition, comprising aneffective amount a compound described herein and a pharmaceuticallyacceptable carrier. In an embodiment, compound is administered to thesubject using a pharmaceutically-acceptable formulation, e.g., apharmaceutically-acceptable formulation that provides sustained deliveryof the compound to a subject for at least 12 hours, 24 hours, 36 hours,48 hours, one week, two weeks, three weeks, or four weeks after thepharmaceutically-acceptable formulation is administered to the subject.

Actual dosage levels and time course of administration of the activeingredients in the pharmaceutical compositions of this invention may bevaried so as to obtain an amount of the active ingredient which iseffective to achieve the desired therapeutic response for a particularpatient, composition, and mode of administration, without being toxic(or unacceptably toxic) to the patient.

In use, at least one compound according to the present invention isadministered in a pharmaceutically effective amount to a subject in needthereof in a pharmaceutical carrier by intravenous, intramuscular,subcutaneous, or intracerebroventricular injection or by oraladministration or topical application. In accordance with the presentinvention, a compound of the invention may be administered alone or inconjunction with a second, different therapeutic. By “in conjunctionwith” is meant together, substantially simultaneously or sequentially.In one embodiment, a compound of the invention is administered acutely.The compound of the invention may therefore be administered for a shortcourse of treatment, such as for about 1 day to about 1 week. In anotherembodiment, the compound of the invention may be administered over alonger period of time to ameliorate chronic disorders, such as, forexample, for about one week to several months depending upon thecondition to be treated.

By “pharmaceutically effective amount” as used herein is meant an amountof a compound of the invention, high enough to significantly positivelymodify the condition to be treated but low enough to avoid serious sideeffects (at a reasonable benefit/risk ratio), within the scope of soundmedical judgment. A pharmaceutically effective amount of a compound ofthe invention will vary with the particular goal to be achieved, the ageand physical condition of the patient being treated, the severity of theunderlying disease, the duration of treatment, the nature of concurrenttherapy and the specific compound employed. For example, atherapeutically effective amount of a compound of the inventionadministered to a child or a neonate will be reduced proportionately inaccordance with sound medical judgment. The effective amount of acompound of the invention will thus be the minimum amount which willprovide the desired effect.

A decided practical advantage of the present invention is that thecompound may be administered in a convenient manner such as byintravenous, intramuscular, subcutaneous, oral orintra-cerebroventricular injection routes or by topical application,such as in creams or gels. Depending on the route of administration, theactive ingredients which comprise a compound of the invention may berequired to be coated in a material to protect the compound from theaction of enzymes, acids and other natural conditions which mayinactivate the compound. In order to administer a compound of theinvention by other than parenteral administration, the compound can becoated by, or administered with, a material to prevent inactivation.

The compound may be administered parenterally or intraperitoneally.Dispersions can also be prepared, for example, in glycerol, liquidpolyethylene glycols, and mixtures thereof, and in oils.

Some examples of substances which can serve as pharmaceutical carriersare sugars, such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethycellulose, ethylcellulose and cellulose acetates; powderedtragancanth; malt; gelatin; talc; stearic acids; magnesium stearate;calcium sulfate; vegetable oils, such as peanut oils, cotton seed oil,sesame oil, olive oil, corn oil and oil of theobroma; polyols such aspropylene glycol, glycerine, sorbitol, mannitol, and polyethyleneglycol; agar; alginic acids; pyrogen-free water; isotonic saline; andphosphate buffer solution; skim milk powder; as well as other non-toxiccompatible substances used in pharmaceutical formulations such asVitamin C, estrogen and echinacea, for example. Wetting agents andlubricants such as sodium lauryl sulfate, as well as coloring agents,flavoring agents, lubricants, excipients, tableting agents, stabilizers,anti-oxidants and preservatives, can also be present. Solubilizingagents, including for example, cremaphore and beta-cyclodextrins canalso used in the pharmaceutical compositions herein.

Pharmaceutical compositions comprising the active compounds of thepresently disclosed subject matter (or prodrugs thereof) can bemanufactured by means of conventional mixing, dissolving, granulating,dragee-making levigating, emulsifying, encapsulating, entrapping orlyophilization processes. The compositions can be formulated inconventional manner using one or more physiologically acceptablecarriers, diluents, excipients or auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically.

Pharmaceutical compositions of the presently disclosed subject mattercan take a form suitable for virtually any mode of administration,including, for example, topical, ocular, oral, buccal, systemic, nasal,injection, transdermal, rectal, vaginal, and the like, or a formsuitable for administration by inhalation or insufflation.

For topical administration, the active compound(s) or prodrug(s) can beformulated as solutions, gels, ointments, creams, suspensions, and thelike.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal, oral, or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions also can contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection canbe presented in unit dosage form (e.g., in ampules or in multidosecontainers) and can contain B added preservatives.

Alternatively, the injectable formulation can be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile pyrogen free water, buffer, dextrose solution, and the like,before use. To this end, the active compound(s) can be dried by anyart-known technique, such as lyophilization, and reconstituted prior touse.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions can take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulfate). The tablets can be coated by methods well known in theart with, for example, sugars or enteric coatings.

Liquid preparations for oral administration can take the form of, forexample, elixirs, solutions, syrups or suspensions, or they can bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations can be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol or fractionated vegetable oils); and preservatives (e.g., methylor propyl p-hydroxybenzoates or sorbic acid). The preparations also cancontain buffer salts, preservatives, flavoring, coloring and sweeteningagents as appropriate.

Preparations for oral administration can be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions can take the form of tabletsor lozenges formulated in a conventional manner.

For rectal and vaginal routes of administration, the active compound(s)can be formulated as solutions (for retention enemas), suppositories, orointments containing conventional suppository bases, such as cocoabutter or other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s) or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit canbe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A specific example of an aqueous suspension formulation suitable fornasal administration using commercially-available nasal spray devicesincludes the following ingredients: active compound or prodrug (0.5-20mg/ml); benzalkonium chloride (0.1-0.2 mg/mL); polysorbate 80 (TWEEN®80; 0.5-5 mg/ml); carboxymethylcellulose sodium or microcrystallinecellulose (1-15 mg/ml); phenylethanol (1-4 mg/ml); and dextrose (20-50mg/ml). The pH of the final suspension can be adjusted to range fromabout pH5 to pH7, with a pH of about pH 5.5 being typical.

For ocular administration, the active compound(s) or prodrug(s) can beformulated as a solution, emulsion, suspension, and the like, suitablefor administration to the eye. A variety of vehicles suitable foradministering compounds to the eye are known in the art. Specificnon-limiting examples are described in U.S. Pat. No. 6,261,547; U.S.Pat. No. 6,197,934; U.S. Pat. No. 6,056,950; U.S. Pat. No. 5,800,807;U.S. Pat. No. 5,776,445; U.S. Pat. No. 5,698,219; U.S. Pat. No.5,521,222; U.S. Pat. No. 5,403,841; U.S. Pat. No. 5,077,033; U.S. Pat.No. 4,882,150; and U.S. Pat. No. 4,738,851, each of which isincorporated herein by reference in its entirety.

For prolonged delivery, the active compound(s) or prodrug(s) can beformulated as a depot preparation for administration by implantation orintramuscular injection. The active ingredient can be formulated withsuitable polymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptioncan be used. To this end, permeation enhancers can be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. No. 5,407,713; U.S. Pat.No. 5,352,456; U.S. Pat. No. 5,332,213; U.S. Pat. No. 5,336,168; U.S.Pat. No. 5,290,561; U.S. Pat. No. 5,254,346; U.S. Pat. No. 5,164,189;U.S. Pat. No. 5,163,899; U.S. Pat. No. 5,088,977; U.S. Pat. No.5,087,240; U.S. Pat. No. 5,008,110; and U.S. Pat. No. 4,921,475, each ofwhich is incorporated herein by reference in its entirety.

Alternatively, other pharmaceutical delivery systems can be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat can be used to deliver active compound(s) or prodrug(s). Certainorganic solvents such as dimethylsulfoxide (DMSO) also can be employed.

The pharmaceutical compositions can, if desired, be presented in a packor dispenser device which can contain one or more unit dosage formscontaining the active compound(s). The pack can, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice can be accompanied by instructions for administration.

The active compound(s) or prodrug(s) of the presently disclosed subjectmatter, or compositions thereof, will generally be used in an amounteffective to achieve the intended result, for example in an amounteffective to treat or prevent the particular disease being treated. Thecompound(s) can be administered therapeutically to achieve therapeuticbenefit or prophylactically to achieve prophylactic benefit. Bytherapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated and/or eradication or amelioration ofone or more of the symptoms associated with the underlying disorder suchthat the patient reports an improvement in feeling or condition,notwithstanding that the patient can still be afflicted with theunderlying disorder. For example, administration of a compound to apatient suffering from an allergy provides therapeutic benefit not onlywhen the underlying allergic response is eradicated or ameliorated, butalso when the patient reports a decrease in the severity or duration ofthe symptoms associated with the allergy following exposure to theallergen. As another example, therapeutic benefit in the context ofasthma includes an improvement in respiration following the onset of anasthmatic attack, or a reduction in the frequency or severity ofasthmatic episodes. Therapeutic benefit also includes halting or slowingthe progression of the disease, regardless of whether improvement isrealized.

For prophylactic administration, the compound can be administered to apatient at risk of developing one of the previously described diseases.A patient at risk of developing a disease can be a patient havingcharacteristics placing the patient in a designated group of at riskpatients, as defined by an appropriate medical professional or group. Apatient at risk may also be a patient that is commonly or routinely in asetting where development of the underlying disease that may be treatedby administration of a metalloenzyme inhibitor according to theinvention could occur. In other words, the at risk patient is one who iscommonly or routinely exposed to the disease or illness causingconditions or may be acutely exposed for a limited time. Alternatively,prophylactic administration can be applied to avoid the onset ofsymptoms in a patient diagnosed with the underlying disorder.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, whether the desired benefit isprophylactic or therapeutic, the severity of the indication beingtreated and the age and weight of the patient, the bioavailability ofthe particular active compound, and the like. Determination of aneffective dosage is well within the capabilities of those skilled in theart.

Effective dosages can be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals can be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC50 of the particular compound as measured in asin vitro assay, such as the in vitro fungal MIC or MFC and other invitro assays described in the Examples section. Calculating dosages toachieve such circulating blood or serum concentrations taking intoaccount the bioavailability of the particular compound is well withinthe capabilities of skilled artisans. For guidance, see Fingl &Woodbury, “General Principles,” In: Goodman and Gilman's ThePharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latestedition, Pagamonon Press, and the references cited therein, which areincorporated herein by reference.

Initial dosages also can be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art.

Dosage amounts will typically be in the range of from about 0.0001 or0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but can be higher orlower, depending upon, among other factors, the activity of thecompound, its bioavailability, the mode of administration, and variousfactors discussed above. Dosage amount and interval can be adjustedindividually to provide plasma levels of the compound(s) which aresufficient to maintain therapeutic or prophylactic effect. In cases oflocal administration or selective uptake, such as local topicaladministration, the effective local concentration of active compound(s)cannot be related to plasma concentration. Skilled artisans will be ableto optimize effective local dosages without undue experimentation.

The compound(s) can be administered once per day, a few or several timesper day, or even multiple times per day, depending upon, among otherthings, the indication being treated and the judgment of the prescribingphysician.

Preferably, the compound(s) will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of thecompound(s) can be determined using standard pharmaceutical procedures.The dose ratio between toxic and therapeutic (or prophylactic) effect isthe therapeutic index. Compounds(s) that exhibit high therapeuticindices are preferred.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof. Therecitation of an embodiment herein includes that embodiment as anysingle embodiment or in combination with any other embodiments orportions thereof.

Agricultural Applications

The compounds and compositions herein can be used in methods ofmodulating metalloenzyme activity in a microorganism on a plantcomprising contacting a compound herein with the plant (e.g., seed,seedling, grass, weed, grain). The compounds and compositions herein canbe used to treat a plant, field or other agricultural area (e.g., asherbicides, pesticides, growth regulators, etc.) by administering thecompound or composition (e.g., contacting, applying, spraying,atomizing, dusting, etc.) to the subject plant, field or otheragricultural area. The administration can be either pre- orpost-emergence. The administration can be either as a treatment orpreventative regimen.

One aspect is a method of treating or preventing a fungal disease ordisorder in or on a plant comprising contacting a compound of any of theformulae herein with the plant. Another aspect is a method of treatingor preventing fungi growth in or on a plant comprising contacting acompound of any of the formulae herein with the plant. Another aspect isa method of inhibiting microorganisms in or on a plant comprisingcontacting a compound of any of the formulae herein with the plant.

The compositions comprising compounds herein can be employed, forexample, in the form of directly sprayable aqueous solutions, powders,suspensions, also highly-concentrated aqueous, oily or other suspensionsor dispersions, emulsions, oil dispersions, pastes, dusts, materials forspreading or granules, by means of spraying, atomizing, dusting,spreading or pouring.

Aqueous use forms can be prepared from emulsion concentrates,suspensions, pastes, wettable powders or water-dispersible granules byadding water. To prepare emulsions, pastes or oil dispersions, thesubstances, as such or dissolved in an oil or solvent, can behomogenized in water by means of wetting agent, tackifier, dispersant oremulsifier. However, it is also possible to prepare concentratescomposed of active substance, wetting agent, tackifier, dispersant oremulsifier and, if appropriate, solvent or oil, and these concentratesare suitable for dilution with water.

Granules, e.g. coated granules, impregnated granules and homogeneousgranules, can be prepared by binding the active ingredients (e.g.,compounds herein) to solid carriers. Solid carriers are mineral earthssuch as silicas, silica gels, silicates, talc, kaolin, limestone, lime,chalk, bole, loess, clay, dolomite, diatomaceous earth, calcium sulfate,magnesium sulfate, magnesium oxide, ground synthetic material,fertilizers such as ammonium sulfate, ammonium phosphate, ammoniumnitrate, ureas and products of vegetable origin such as cereal meal,tree bark meal, wood meal and nutshell meal, cellulose powders or othersolid carriers.

The compounds herein can be formulated as ordinary tablets, capsules,solids, liquids, emulsions, slurries, oils, fine granules or powders,which are suitable for administration to plants, fields or otheragricultural areas. In preferred embodiments, the preparation includesbetween 1 and 95% (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 25%, 75%, 80%,90%, 95%) compound herein in a carrier or diluent. The compositionsdelineated herein include the compounds of the formulae delineatedherein, as well as additional agricultural agents if present, in amountseffective for controlling (e.g., modulating, inhibiting) ametalloenzyme-mediated agricultural disease or disorder.

In one approach, a compound herein is provided in an encapsulatedformulation (liquid or powder). Specific materials suitable for use incapsule materials include, but are not limited to, porous particulatesor substrates such as silica, perlite, talc, clay, pyrophyllite,diatomaceous earth, gelatin and gels, polymers (e.g., polyurea,polyurethane, polyamide, polyester, etc.), polymeric particles, orcellulose. These include, for example, hollow fibers, hollow tubes ortubing which release a compound specified herein through the walls,capillary tubing which releases the compound out of an opening in thetubing, polymeric blocks of different shapes, e.g., strips, blocks,tablets, discs, which release the compound out of the polymer matrix,membrane systems which hold the compound within an impermeable containerand release it through a measured permeable membrane, and combinationsof the foregoing. Examples of such dispensing compositions are polymerlaminates, polyvinyl chloride pellets, and microcapillaries.

Encapsulation processes are typically classified as chemical ormechanical. Examples of chemical processes for encapsulation include,but are not limited to, complex coacervation, polymer-polymerincompatibility, interfacial polymerization in liquid media, in situpolymerization, in-liquid drying, thermal and ionic gelation in liquidmedia, desolvation in liquid media, starch-based chemistry processes,trapping in cyclodextrins, and formation of liposomes. Examples ofmechanical processes for encapsulation include, but are not limited to,spray drying, spray chilling, fluidized bed, electrostatic deposition,centrifugal extrusion, spinning disk or rotational suspensionseparation, annular-jet encapsulation, polymerization at liquid-gas orsolid-gas interface, solvent evaporation, pressure extrusion or sprayinginto solvent extraction bath. Microcapsules are also suitable for thelong-term release of active compound herein.

Microcapsules are small particles that contain a core material or activeingredient surrounded by a coating or shell. The size of themicrocapsule typically varies from 1 to 1000 microns with capsulessmaller than 1 micron classified as nanocapsules and capsules largerthan 1000 microns as macrocapsules. Core payload usually varies from 0.1to 98 weight percent. Microcapsules can have a variety of structures(continuous core/shell, multinuclear, or monolithic) and have irregularor geometric shapes.

In another approach, the compound herein is provided in an oil-baseddelivery system. Oil release substrates include vegetable and/or mineraloils. In one embodiment, the substrate also contains a surface activeagent that renders the composition readily dispersable in water; suchagents include wetting agents, emulsifying agents, dispersing agents,and the like.

Compounds of the invention can also be provided as emulsions. Emulsionformulations can be found as water in oil (w/o) or oil in water (o/w).Droplet size can vary from the nanometer scale (colloidal dispersion) toseveral hundred microns. A variety of surfactants and thickeners areusually incorporated in the formulation to modify the size of thedroplets, stabilize the emulsion, and modify the release.

Alternatively, compounds of the invention may also be formulated in asolid tablet and comprise (and preferably consist essentially of) anoil, a protein/carbohydrate material (preferably vegetable based), asweetener and an active ingredient useful in the prevention or treatmentof a metalloenzyme-mediated agricultural disease or disorder. In oneembodiment the invention provides a solid tablet and comprises (andpreferably consist essentially of) an oil, a protein/carbohydratematerial (preferably vegetable based), a sweetener and an activeingredient (e.g., compound herein or combinations or derivativesthereof) useful in the prevention or treatment a metalloenzyme-mediatedagricultural disease or disorder. Tablets typically contain about 4-40%(e.g., 5%, 10%, 20%, 30%, 40%) by weight of an oil (e.g., plant oil,such as corn, sunflower, peanut, olive, grape seed, tung, turnip,soybean, cotton seed, walnut, palm, castor, earth almond, hazelnut,avocado, sesame, croton tiglium, cacao, linseed, rape-seed, and canolaoils and their hydrogenated derivatives; petroleum derived oils (e.g.,paraffins and petroleum jelly), and other water immiscible hydrocarbons(e.g., paraffins). The tablets further contain from about 5-40% (e.g.,5%, 10%, 20%, 30%, 40%) by weight of a vegetable-basedprotein/carbohydrate material. The material contains both a carbohydrateportion (e.g., derived from cereal grains, such as wheat, rye, barley,oat, corn, rice, millet, sorghum, birdseed, buckwheat, alfalfa, mielga,corn meal, soybean meal, grain flour, wheat middlings, wheat bran, corngluten meal, algae meal, dried yeast, beans, rice) and a proteinportion.

Optionally, various excipients and binders can be used in order toassist with delivery of the active ingredient or to provide theappropriate structure to the tablet. Preferred excipients and bindersinclude anhydrous lactose, microcrystalline cellulose, corn starch,magnesium estearate, calcium estearate, zinc estearate, sodiccarboxymethylcellulose, ethyl cellulose, hydroxypropyl methyl cellulose,and mixtures thereof.

The invention provides kits for the treatment or prevention ofagricultural or plant disease or disorders. In one embodiment, the kitincludes a composition containing an effective amount of a compoundherein in a form suitable for delivery to a site plant. In someembodiments, the kit comprises a container which contains a compound anyof the formulae herein (e.g., formula I or formula II); such containerscan be boxes, ampules, bottles, vials, tubes, bags, pouches,blister-packs, or other suitable container forms known in the art. Suchcontainers can be made of plastic, glass, laminated paper, metal foil,or other materials suitable for holding compounds.

If desired the compound(s) of the invention is provided together withinstructions for administering it to a plant, field, or otheragricultural area. The instructions will generally include informationabout the use of the composition for the treatment or prevention of ametalloenzyme-mediated agricultural disease or disorder. In otherembodiments, the instructions include at least one of the following:description of the compound; dosage schedule and administration fortreatment or prevention of a metalloenzyme-mediated agricultural diseaseor disorder; precautions; warnings; description of research studies;and/or references. The instructions may be printed directly on thecontainer (when present), or as a label applied to the container, or asa separate sheet, pamphlet, card, or folder supplied in or with thecontainer.

EXAMPLES

The present invention will now be demonstrated using specific examplesthat are not to be B construed as limiting.

General Experimental Procedures

Definitions of variables in the structures in schemes herein arecommensurate with those of corresponding positions in the formulaedelineated herein.

Synthesis of Azoles

Syntheses of alkyne targets (I) may be accomplished using the examplesynthesis that is shown below (Scheme 1). A broad range of arenes andheterocycles (R₁₁=aryl or heteroaryl), may be prepared starting fromaryl-bromides starting materials (e.g. 1). For the purpose of thisexample, R₄ is a halogenated benzene moiety. An example synthesis oftargets (I) commences with condensation of 2,5-dibromo-pyridine withcopper-activated ethyl α-bromo-acetate followed by condensation of theincipient ethyl ester product with lithiated bromodifluorobenzene tofurnish ketone B (Scheme 1). The ketone is epoxidized with diazomethaneto afford C. The 1-tetrazole product D (and 2-tetrazole isomer) isobtained by opening the epoxide C with tetrazole in the presence ofpotassium carbonate. The resultant pyridyl-bromide D is treated withphenyl-acetylenes to give coupled products (e.g. 1).

In embodiments, the invention provides for the intermediate compounds ofthe formulae delineated herein and methods of converting such compoundsto compounds of the formulae herein (e.g., in Scheme 1, A to B; B to D;C to 1; or D to 1) comprising reacting a compound herein with one ormore reagents in one or more chemical transformations (including thoseprovided herein) to thereby provide the compound of any of the formulaeherein or an intermediate compound thereof.

The synthetic methods described herein may also additionally includesteps, either before or after any of the steps described in any scheme,to add or remove suitable protecting groups in order to ultimately allowsynthesis of the compound of the formulae described herein. The methodsdelineated herein contemplate converting compounds of one formula tocompounds of another formula (e.g., in Scheme 1, A to B; B to D; C to 1;or D to 1). The process of converting refers to one or more chemicaltransformations, which can be performed in situ, or with isolation ofintermediate compounds. The transformations can include reacting thestarting compounds or intermediates with additional reagents usingtechniques and protocols known in the art, including those in thereferences cited herein. Intermediates can be used with or withoutpurification (e.g., filtration, distillation, sublimation,crystallization, trituration, solid phase extraction, andchromatography).

Example 12-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(phenylethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(1)

To a suspension of copper powder (2.68 g, 42.2 mmol) in DMSO (35 mL) wasadded ethyl bromodifluoroacetate (2.70 mL, 21.10 mmol), and the mixturewas stirred for 1 h at RT. 2,5-Dibromopyridine (2.50 g, 10.55 mmol) wasthen added and continued stirring for 15 h at RT. The reaction wasquenched with aqueous NH₄Cl and extracted with DCM (3×25 mL). Thecombined organic layers were washed with water, washed with brine, driedover anhydrous Na₂SO₄, and concentrated under reduced pressure to affordcrude product mixture which upon column purification using EtOAc/hexaneafforded the ethyl ester intermediate (2.40 g, 8.57 mmol, 81%) as a paleyellow oil. ¹H NMR (500 MHz, CDCl₃): δ 8.71 (s, 1H), 8.00 (d, J=9.0 Hz,1H), 7.64 (d, J=9.0 Hz, 1H), 4.42-4.35 (m, 2H), 1.39-1.31 (m, 3H).

To a stirred solution of 2,4-difluoro-bromobenzene (1.65 g, 8.57 mmol)in diethyl ether (10 mL) was added n-BuLi (3.70 mL, 8.57 mmol) at −70°C. followed by addition of ester (2.40 g, 8.57 mmol) in diethyl ether (5mL) after 15 minutes. The reaction mixture was stirred for 1 h at −70°C. and warmed to room temperature at which point another 2 h stirringwas employed. The reaction was quenched with aqueous NH₄Cl solution andextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with water, washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The crude compound was purified bycolumn chromatography to afford ketone B (1.30 g, 3.73 mmol, 43%) asyellow liquid. ¹H NMR (500 MHz, CDCl₃): δ 8.62 (s, 1H), 8.08-8.04 (m,2H), 7.74-7.70 (m, 1H), 7.05-6.95 (m, 1H), 6.88-6.78 (m, 1H). MS (ESI):347, 349 [(M⁺+1)+2].

To a stirred solution of ketone B (1.30 g, 3.73 mmol) in diethyl ether(300 mL) was added freshly prepared diazomethane at 0° C. followed bywarming to RT. The reaction mixture was stirred for 2 h. The volatileswere removed under reduced pressure to afford a crude product mixturewhich upon column chromatography using EtOAc/hexane as the eluentafforded oxirane C (800 mg, 2.20 mmol, 59%) as light yellow solid. ¹HNMR (500 MHz, CDCl₃): δ 8.72 (s, 1H), 7.89 (d, J=9.0 Hz, 1H), 7.39-7.35(m, 2H), 6.86-6.83 (m, 1H), 6.77-6.74 (m, 1H), 3.44 (s, 1H), 2.98 (s,1H). MS (ESI): 362, 364 [(M⁺+1)+2].

To a stirred solution of epoxide C (5 g, 13.8 mmol) in DMF (15 mL) wasadded K₂CO₃ (1.9 g, 13.87 mmol) followed by 1H-tetrazole (1.55 g, 20.72mmol) at RT. The resulting reaction mixture was heated to 70° C. andstirred for 16 h. The progress of the reaction was monitored by TLC. Thereaction was quenched with ice-cold water (50 mL) and extracted withethyl acetate (3×50 mL). The combined organic layer was washed withwater (30 mL), brine (30 mL) and dried over anhydrous Na₂SO₄ to obtain acrude product which was purified by silica gel column chromatographyeluting with 40% EtOAc/hexane to afford 1-tetrazole product D (2.7 g,6.24 mmol, 45.3%) as white solid. ¹H NMR (500 MHz, CDCl₃): 8.73 (s, 1H),8.62 (s, 1H), 7.95 (dd, J=2.0 Hz, 8.0 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H),7.31-7.28 (m, 1H), 6.86 (s, 1H), 6.77-6.73 (m, 1H), 6.70-6.66 (m, 1H),5.60 (d, J=14.5 Hz, 1H), 5.11 (d, J=14.5 Hz, 1H).

Mass: m/z 433.3 [M⁺+2]

To a stirred solution of compound D (100 mg, 0.23 mmol) in DMF (2 mL)were added phenyl acetylene (35 mg, 0.34 mmol) followed by TPP (6 mg,0.023 mmol), Pd(PPh₃)₂Cl₂ (16 mg, 0.023 mmol), CuI (4 mg, 0.023 mmol)and Et₃N (5 mL) at RT and purged with argon for a period of 30 min andthe stirring was continued for 16 h at RT. The reaction mixture wascooled to RT, filtered through a pad of celite and the filtrate wasconcentrated under reduced pressure. Thus obtained residue was dilutedwith water (50 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organic layer was washed with water (15 mL), brine (15 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford the crude product. The crude product was purified by silica gelcolumn chromatography eluting with gradients of EtOAc/hexane to afford 1(30 mg, 0.06 mmol, 28%) as off-white solid. ¹H NMR (500 MHz, CDCl₃): δ8.75 (s, 1H), 8.65 (s, 1H), 7.88 (dd, J=2.0 Hz, 8.5 Hz, 1H), 7.55-7.53(m, 3H), 7.41-7.37 (m, 3H), 7.31-7.26 (m, 2H), 6.76-6.75 (m, 1H),6.66-6.64 (m, 1H), 5.61 (d, J=14.0 Hz, 1H), 5.12 (d, J=14.0 Hz, 1H).HPLC: 96.4%. MS (ESI): m/z 453 [M⁺+1].

Example 2

1-(5-((4-Chlorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(2)

To a stirred solution of compound D (100 mg, 0.231 mmol) in THF (5 mL)were added 4-chloro phenyl acetylene (47 mg, 0.345 mmol) followed byPd(PPh₃)₂Cl₂ (16 mg, 0.023 mmol), CuI (4.4 mg, 0.023 mmol) anddiisopropyl ethylamine (0.08 mL, 0.462 mmol) at RT under argonatmosphere. The resulting reaction mixture was stirred for 16 h atreflux temperature under argon atmosphere. The progress of the reactionwas monitored by TLC and LC-MS. The reaction mixture was cooled to RT,filtered through a pad of celite and filtrate was concentrated underreduced pressure. The obtained residue was diluted with water (15 mL)and extracted with ethyl acetate (4×30 mL). The combined organic layerwas washed with water (10 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the crude product. Thecrude product was purified by prep HPLC (mobile phase: CH₃CN:0.1% TFA inH₂O, gradient; flow Rate: 15.0 mL/min) to afford 2 (14 mg, 0.028 mmol,12.5%) as pale yellow solid. ¹H NMR (500 MHz, CDCl₃): δ 8.75 (s, 1H),8.64 (s, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 2H), 7.47 (d,J=9.0 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.33-7.28 (m, 1H), 6.78-6.74 (m,1H), 6.68-6.65 (m, 1H), 5.60 (d, J=14.5 Hz, 1H), 5.13 (d, J=14.5 Hz,1H). HPLC: 99.5%. MS (ESI): m/z 488 [M⁺+1].

Example 3

2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(3)

To a stirred solution of compound D (250 mg, 0.578 mmol) in DMF (5 mL)were added 4-fluoro phenyl acetylene (104 mg, 0.868 mmol) followed byTPP (15 mg, 0.0578 mmol), CuI (11 mg, 0.0578 mmol) and Et₃N (16 mL) atRT and purged with argon for a period of 20 min. To the resultingreaction mixture was added Pd(PPh₃)₂Cl₂ (40 mg, 0.0578 mmol), againpurged with argon for 20 min and stirred at RT. After 16 h, only 0.87%conversion was observed by LC-MS; the reaction mixture was then slowlyheated to 60° C. and stirred for 6 h. After 6 h, the reaction mixturewas cooled to RT, filtered through a pad of celite and filtrate wasconcentrated under reduced pressure. The obtained residue was dilutedwith water (50 mL) and extracted with ethyl acetate (3×40 mL). Thecombined organic layer was washed with water (2×15 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford thecrude product. The crude product was purified by silica gel columnchromatography eluting with 35% EtOAc/hexane to afford 3 (25 mg, 0.053mmol, 9.2%) as off-white solid. ¹H NMR (500 MHz, CDCl₃): δ 8.75 (s, 1H),8.63 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.55-7.51 (m, 2H), 7.33-7.27 (m,2H), 7.09 (t, J=8.0 Hz, 2H), 6.78-6.74 (m, 1H), 6.68-6.65 (m, 1H), 5.61(d, J=14.5 Hz, 1H), 5.13 (d, J=14.5 Hz, 1H). HPLC: 92.97%. MS (ESI): m/z472.4 [M⁺+1].

Example 4

2-(2,4-Difluorophenyl)-1-(5-((2,4-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(4)

To a stirred solution of compound D (100 mg, 0.231 mmol) in DMF (3 mL)were added 2,4-difluoro phenyl acetylene (47.9 mg, 0.347 mmol) followedby TPP (6 mg, 0.023 mmol), CuI (4.39 mg, 0.023 mmol) at RT and purgedwith argon for a period of 20 min. To the resulting reaction mixture wasadded Pd(PPh₃)₂Cl₂ (16.24 mg, 0.023 mmol) again purged with argon for 15min and stirred for 16 h at RT. The reaction mixture was cooled to RT,filtered through a pad of celite and filtrate was concentrated underreduced pressure. The obtained residue was diluted with water (20 mL)and extracted with ethyl acetate (4×20 mL). The combined organic layerwas washed with water (2×10 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the crude product. Thecrude product was purified by prep HPLC (mobile phase: (A) CH₃CN (B)0.1% TFA in H₂O, isocratic: A:B=70:30; flow Rate: 15.0 mL/min) to afford4 (18 mg, 0.036 mmol, 15.9%) as off-white solid. ¹H NMR (500 MHz,CDCl₃): δ 8.75 (s, 1H), 8.66 (s, 1H), 7.91 (dd, J=1.5 Hz, 8.0 Hz, 1H),7.56 (d, J=8.0 Hz, 1H), 7.53-7.49 (m, 1H), 7.32-7.27 (m, 1H), 6.94-6.88(m, 2H), 6.78-6.74 (m, 1H), 6.69-6.65 (m, 1H), 5.61 (d, J=14.0 Hz, 1H),5.13 (d, J=14.0 Hz, 1H). HPLC: 99.7%. MS (ESI): m/z 490 [M⁺+1].

Example 5

2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(trifluoromethyl)phenyl)ethynyl)pyridin-2-yl)propan-2-ol (5)

To a stirred solution of compound D (300 mg, 0.69 mmol) in DMF (5 mL)were added 4-(trifluoromethyl) phenyl acetylene (177 mg, 1.0 mmol)followed by TPP (18 mg, 0.069 mmol), CuI (13 mg, 0.069 mmol),Pd(PPh₃)₂Cl₂ (48 mg, 0.069 mmol) and Et₃N (10 mL) at RT and purged withargon for a period of 30 min. The resulting reaction mixture was stirredfor 16 h at RT. The reaction mixture was cooled to RT, filtered througha pad of celite and the filtrate was concentrated under reducedpressure. The obtained residue was diluted with water (50 mL) andextracted with ethyl acetate (3×40 mL). The combined organic layer waswashed with water (2×20 mL), brine (20 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product. Thecrude product was purified by prep HPLC (mobile phase: CH₃CN:0.1% TFA inH₂O, gradient; flow Rate: 15.0 mL/min) to afford 5 (18 mg, 0.034 mmol,5%) as pale yellow solid. ¹H NMR (500 MHz, CDCl₃): δ 8.75 (s, 1H), 8.66(s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.65 (s, 3H), 7.53 (d, J=8.5 Hz, 1H),7.34-7.29 (m, 1H), 6.78-6.74 (m, 1H), 6.69-6.66 (m, 1H), 5.61 (d, J=14.5Hz, 1H), 5.15 (d, J=14.5 Hz, 1H). HPLC: 99.3%. MS (ESI): m/z 522.3[M⁺+1].

Preparation of Tributyltin Intermediate G

To a stirred solution of compound C (20.0 g, 55.24 mmol) in THF (300 mL)were added TMS-acetylene (10.3 mL, 82.87 mmol) followed by CuI (525 mg,2.76 mmol), Pd(PPh₃)₂Cl₂ (1.93 g, 2.76 mmol) and Et₃N (20 mL) at RTunder inert atmosphere and stirred for 16 h; progress of the reactionwas monitored by TLC. The reaction mixture was filtered through a pad ofcelite and washed with EtOAc (3×100 mL). The filtrate was washed withwater (150 mL), brine (150 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to obtain the crude. The crudematerial was purified by silica gel column chromatography (eluent: 7%EtOAc/hexanes) to afford compound E (18.0 g, 47.5 mmol, 85%) as paleyellow solid. ¹H NMR (400 MHz, CDCl₃): δ 8.69 (s, 1H), 7.78 (d, J=10.0Hz, 1H), 7.76 (d, J=10.0 Hz, 1H), 7.37-7.31 (m, 1H), 6.85-6.80 (m, 1H),6.76-6.71 (m, 1H), 3.45 (d, J=5.0 Hz, 1H), 2.96 (d, J=5.0 Hz, 1H), 0.26(s, 9H).

To a stirred solution of E (18.0 g, 47.5 mmol) in THF (200 mL) was addedTBAF (52.2 mL, 52.25 mmol; 1M solution in THF) at 0° C. under inertatmosphere and stirred for 1 h; progress of the reaction was monitoredby TLC. The volatiles were then evaporated under reduced pressure; theobtained residue was diluted with EtOAc (500 mL), washed with water (250mL), brine (250 mL), dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to obtain the crude. The crude material was purified bysilica gel column chromatography (eluent: 8-10% EtOAc/hexanes) to affordcompound F (9.0 g, 29.31 mmol, 61.7%) as pale yellow solid.

¹H NMR (400 MHz, CDCl₃): δ 8.73 (d, J=1.5 Hz, 1H), 7.82 (dd, J=8.0, 1.5Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.38-7.34 (m, 1H), 6.85-6.81 (m, 1H),6.76-6.72 (m, 1H), 3.44 (d, J=5.0 Hz, 1H), 3.31 (s, 1H), 2.97 (d, J=5.0Hz, 1H).

To a stirred solution of compound F (9.0 g, 29.31 mmol) in Et₂O (200 mL)was added n-BuLi (22.0 mL, 35.18 mmol; 1.6M in hexane) at −78° C. underinert atmosphere. After being stirred at −78° C. for 30 min, n-Bu₃SnCl(11.9 mL, 43.97 mmol) was added. The reaction mixture was allowed towarm to RT and stirred for 16 h. The progress of the reaction wasmonitored by TLC. The reaction mixture was quenched with saturated NH₄Clsolution, extracted with EtOAc (2×200 mL). The combined organic extractswere washed with water (150 mL), brine (150 mL), dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to obtain the crude-G(20.0 g). The crude was used for the next reaction without furtherpurification.

Example 65-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N-(4-fluorobenzyl)thiophene-2-carboxamide (6)

To a stirred solution of acid-H (1.50 g, 7.24 mmol) in DMF (20 mL) wasadded 4-fluoro benzyl amine (1.35 g, 10.84 mmol) followed by HOBt (1.08g, 7.95 mmol) and DIPEA (3 mL, 18.07 mmol) under inert atmosphere at RTand stirred for 5 min. Then, EDCl (1.52 g, 7.96 mmol) was added to thereaction mixture and continued stirring for 16 h; progress of thereaction was monitored by TLC. The reaction mixture was then dilutedwith EtOAc (100 mL) and washed with 0.1N HCl (100 mL). The separatedorganic layer was washed with saturated NaHCO₃ solution (100 mL), brine(100 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to obtain the crude. The crude material was purified by silicagel column chromatography (eluent: 20% EtOAc/hexane) to afford theamide-I (1.5 g, 4.77 mmol, 66%) as colorless oil. ¹H NMR (400 MHz,CDCl₃): δ 7.31-7.28 (m, 2H), 7.23 (d, J=4.0 Hz, 1H), 7.05-6.99 (m, 3H),6.21 (bs, 1H), 4.55 (d, J=5.6 Hz, 2H).

To a stirred solution of compound G (4.0 g, crude) in 1,4-dioxane (20mL) was added compound I (600 mg, 1.91 mmol) followed by purge withargon for 20 min. Pd(PPh₃)₄ (434 mg, 0.37 mmol) was then added to themixture at RT and purged with argon for another 20 min. The reactionmixture was gradually heated up to 80° C. and stirred for 3 h; progressof the reaction was monitored by TLC. The reaction mixture was allowedto cool to RT and the volatiles were evaporated under reduced pressureto afford the compound J (1.0 g, crude). The crude compound was used forthe next reaction without further purification. ¹H NMR (400 MHz, CDCl₃):δ 8.76 (s, 1H), 7.85 (dd, J=8.0, 2.0 Hz, 1H), 7.47 (d, J=8.0, Hz, 1H),7.40-7.31 (m, 4H), 7.27 (d, J=4.0 Hz, 1H), 7.06-7.02 (m, 2H), 6.86-6.81(m, 1H), 6.77-6.71 (m, 1H), 6.25 (t, J=5.6 Hz, 1H), 4.59 (d, J=5.6 Hz,2H), 3.47 (d, J=5.0 Hz, 1H), 2.98 (d, J=5.0 Hz, 1H). LC-MS (ESI): m/z540.0 [M]⁺ at 4.28 RT (86% pure).

To a stirred solution of epoxide J (1.0 g, crude) in dry DMF (10 mL) wasadded 1H-tetrazole (194 mg, 2.77 mmol) followed by K₂CO₃ (255 mg, 1.85mmol) at RT under inert atmosphere. The resulting reaction mixture wasgradually heated up to 65° C. and stirred for 16 h; progress of thereaction was monitored by TLC. The reaction mixture was diluted withice-cold water (100 mL) and extracted with EtOAc (2×100 mL). Thecombined organic extracts were washed with water (50 mL), brine (50 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toobtain the crude. The crude material was purified by silica gel columnchromatography (eluted with 45-50% EtOAc/hexanes) to afford 6 (500 mg,0.82 mmol) as pale yellow solid. ¹H-NMR (400 MHz, CDCl₃): δ 8.74 (s,1H), 8.64 (s, 1H), 7.89 (dd, J=8.4, 2.0 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H),7.38 (d, J=4.0 Hz, 1H), 7.35-7.27 (m, 4H), 7.14 (bs, OH), 7.05 (t, J=8.4Hz, 2H), 6.79-6.73 (m, 1H), 6.69-6.64 (m, 1H), 6.22 (t, J=5.6 Hz, 1H),5.59 (d, J=14.0 Hz, 1H), 5.14 (d, J=14.0 Hz, 1H), 4.60 (d, J=5.6 Hz,2H).

Chiral Preparative HPLC Method for the Separation of 6-Enantiomers:

The racemate-6 (303 mg, 0.49 mmol) was separated by preparative highperformance liquid chromatography (CHIRALPAK IA, 250×20 mm, 5μ; using(A) n-Hexane, (B) EtOH (A:B, 75:25) as a mobile phase; Flow rate: 15mL/min) to obtain 6-(+) (100 mg) as off-white solid.

Analytical Data for 6-(+):

Chiral HPLC Purity: 98.5% ee R_(t)=20.22 min (CHIRALPAK IA, 250×4.6 mm,5μ; mobile phase (A) n-Hexane, (B) EtOH (A:B::75:25); flow Rate: 1.00mL/min).

Optical rotation [α]_(D) ²⁰: +19.76° (c=0.1% in MeOH).

1H-NMR (400 MHz, CDCl₃): δ 8.74 (s, 1H), 8.64 (s, 1H), 7.89 (dd, J=8.4,2.0 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.38 (d, J=4.0 Hz, 1H), 7.35-7.27(m, 4H), 7.14 (bs, OH), 7.05 (t, J=8.4 Hz, 2H), 6.79-6.73 (m, 1H),6.69-6.64 (m, 1H), 6.22 (t, J=5.6 Hz, 1H), 5.59 (d, J=14.0 Hz, 1H), 5.14(d, J=14.0 Hz, 1H), 4.60 (d, J=5.6 Hz, 2H). Mass: m/z 611 [M+H]⁺. HPLC:98.5%.

Example 74-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl) pyridin-3-yl) ethynyl) phenoxy) methyl)-2-fluorobenzonitrile (7)

To a stirred solution of 4-bromophenol (K) (1.0 g, 5.78 mmol) in DMF (10mL) were added K₂CO₃ (1.6 g, 11.56 mmol) followed by 4-cyano-3-fluorobenzyl bromide (1.36 g, 6.36 mmol) at RT under inert atmosphere. Theresulting reaction mixture was gradually heated up to 70° C. and stirredfor 3 h; progress of the reaction was monitored by TLC. The reactionmixture was cooled to RT, diluted with ice-cold water (100 mL) andextracted with EtOAc (2×100 mL). The combined organic layers were washedwith water (2×50 mL), brine (100 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to obtain the crude. The crudecompound was purified by silica gel column chromatography (eluent: 15%EtOAc/Hexanes) to afford L (1.2 g, 3.93 mmol, 68%) as brown solid. ¹HNMR (400 MHz, CDCl₃): δ 7.66-7.62 (m, 1H), 7.41 (d, J=6.8 Hz, 2H),7.32-7.29 (m, 2H), 6.82 (d, J=6.8 Hz, 2H), 5.09 (s, 2H). LC-MS: m/z304.7 [M−H]⁻ at 4.80 RT (75.9% pure).

To a stirred solution of compound G (3.0 g, crude) in 1,4-dioxane (15mL) was added L (1.2 g, 3.93 mmol) and purged with inert gas for 15 min.To the resulting reaction mixture was added Pd(PPh₃)₄ (291 mg, 0.25mmol) and purged for another 10 min. The reaction mixture was thengradually heated up to 90° C. and stirred for 3 h; progress of thereaction was monitored by TLC. The reaction mixture was then cooled toRT; volatiles were evaporated under reduced pressure to obtain thecrude. The crude material was purified by silica gel columnchromatography (eluent: 18% EtOAc/hexanes) to afford M (0.7 g, crude) asyellow solid. ¹H NMR (400 MHz, CDCl₃): δ 8.77 (s, 1H), 7.85 (d, J=8.0Hz, 1H), 7.68 (dd, J=8.4, 1.6 Hz, 1H), 7.53 (d, J=6.8 Hz, 2H), 7.46 (d,J=8.0 Hz, 1H), 7.41-7.33 (m, 3H), 6.97 (d, J=6.8 Hz, 2H), 6.88-6.83 (m,1H), 6.77-6.71 (m, 1H), 5.17 (s, 2H), 3.48 (d, J=5.2 Hz, 1H), 3.00 (d,J=5.2 Hz, 1H). LCMS: m/z 533.9 [M+H]⁺ at 5.29 RT (89.0% pure).

To a stirred solution of M (0.7 g, crude) in DMF (7 mL) were added1H-tetrazole (138 mg, 1.97 mmol) followed by K₂CO₃ (181 mg, 1.31 mmol)at RT under inert atmosphere. The resulting reaction mixture wasgradually heated up to 65° C. and stirred for 7 h; progress of thereaction was monitored by TLC. The reaction mixture was cooled to RT;diluted with ice-cold water (50 mL) and extracted with EtOAc (2×50 mL).The combined organic layers were washed with water (2×50 mL), brine (50mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto obtain the crude. The crude compound was purified by silica gelcolumn chromatography (eluent: 40% EtOAc/hexanes) to afford 7 (350 mg,0.58 mmol) as yellow solid. ¹H NMR (500 MHz, CDCl₃): δ 8.75 (s, 1H),8.62 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.53 (d,J=8.0 Hz, 1H), 7.50 (d, J=9.0 Hz, 2H), 7.34-7.32 (m, 4H), 6.95 (d, J=9.0Hz, 2H), 6.77-6.75 (m, 1H), 6.67-6.65 (m, 1H), 5.59 (d, J=14.0 Hz, 1H),5.15 (s, 2H), 5.12 (d, J=14.0 Hz, 1H).

Chiral Preparative HPLC Method for the Separation of Enantiomers of 7:

The enantiomers of 7 (35 mg) were separated by normal-phase preparativehigh performance liquid chromatography (CHIRALPAK IC, 250×20 mm, 5μ;using (A) 0.1% TEA in n-hexane, (B) Ethanol (A:B::70:30) as a mobilephase; Flow rate: 15 mL/min) to obtain 7-(+) (15 mg) as off-white solid.

Analytical Data for 7-(+):

Chiral HPLC: 100% ee R_(t)=27.72 min (Chiralpak IC, 250×4.6 mm, 5μ;mobile phase (A) 0.1% TEA in n-Hexane, (B) Ethanol (A:B::70:30); flowRate: 1.00 mL/min) Optical rotation [α]_(D) ²⁰: +29.80° (c=0.1% inMeOH).

¹H NMR (500 MHz, CDCl₃): δ 8.75 (s, 1H), 8.62 (s, 1H), 7.86 (d, J=8.0Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.50 (d, J=9.0Hz, 2H), 7.34-7.32 (m, 4H), 6.95 (d, J=9.0 Hz, 2H), 6.77-6.75 (m, 1H),6.67-6.65 (m, 1H), 5.59 (d, J=14.0 Hz, 1H), 5.15 (s, 2H), 5.12 (d,J=14.0 Hz, 1H). MS (ESI): 603 [M+H]⁺. HPLC: 99.0%.

Example 84-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)benzonitrile(8)

To a stirred solution of 4-bromophenol (K) (2.9 g, 14.45 mmol) in DMF(20 mL) was added K₂CO₃ (4.0 g, 28.90 mmol) followed by 4-cyano benzylbromide (3.4 g, 17.34 mmol) under inert atmosphere at RT. The mixturewas gradually heated up to 80° C. and stirred for 1 h; progress of thereaction was monitored by TLC. The reaction mixture was cooled to RT,quenched with ice-cold water (100 mL), extracted with EtOAc (2×100 mL).The combined organic layers were washed with water (100 mL), brine (100mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto obtain the crude. The crude material was purified by silica gelcolumn chromatography (eluent: 5% EtOAc/hexane) to afford the compound N(2.9 g, 10.06 mmol, 71%) as colorless liquid. ¹H NMR (400 MHz, CDCl₃): δ7.68 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.39 (d, J=9.2 Hz, 2H),6.83 (d, J=9.2 Hz, 2H), 5.09 (s, 2H).

To a stirred solution of compound G (3.5 g, crude) in 1,4-dioxane (20mL) was added compound N (2.7 g, 9.39 mmol) and purged with argon for 20min. Pd(PPh₃)₄ (678 mg, 0.58 mmol) was added to the mixture at RT andpurged with argon for another 20 min. The reaction mixture was graduallyheated up to 80° C. and stirred for 3 h; progress of the reaction wasmonitored by TLC. The reaction mixture was allowed to cool to RT and thevolatiles were evaporated under reduced pressure to afford the compoundO (800 mg, crude). The crude was used for the next reaction withoutfurther purification. ¹H NMR (500 MHz, CDCl₃): δ 8.74 (s, 1H), 7.81 (d,J=8.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.51 (d,J=9.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.39-7.35 (m, 1H), 6.96 (d, J=9.0Hz, 2H), 6.85-6.82 (m, 1H), 6.76-6.72 (m, 1H), 5.16 (s, 2H), 3.47 (d,J=5.0 Hz, 1H), 2.98 (d, J=5.0 Hz, 1H). Mass (ESI): m/z 515 [M+H]⁺.

To a stirred solution of epoxide O (800 mg, crude) in dry DMF (10 mL)was added 1H-tetrazole (163 mg, 2.33 mmol) followed by K₂CO₃ (215 mg,1.55 mmol) at RT under inert atmosphere. The resulting reaction mixturewas gradually heated up to 65° C. and stirred for 16 h; the progress ofthe reaction was monitored by TLC. The reaction mixture was diluted withice-cold water (50 mL) and extracted with EtOAc (2×50 mL). The combinedorganic extracts were washed with water (50 mL), brine (50 mL), driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to obtainthe crude. The crude material was purified by silica gel columnchromatography (eluted with 40-45% EtOAc/hexanes) to afford 8 (360 mg,0.61 mmol, 39.5%) as yellow solid. ¹H-NMR (400 MHz, CDCl₃): δ 8.76 (s,1H), 8.62 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 2H),7.69-7.51 (m, 3H), 7.47 (d, J=7.5 Hz, 2H), 7.33-7.27 (m, 2H), 6.96 (d,J=7.5 Hz, 2H), 6.78-6.73 (m, 1H), 6.69-6.64 (m, 1H), 5.60 (d, J=14.0 Hz,1H), 5.16 (s, 2H), 5.12 (d, J=14.0 Hz, 1H).

Chiral Preparative HPLC Method for the Separation of 8 Enantiomers(Preparation of 8 (+)):

The enantiomers of 8 (300 mg, 0.51 mmol) were separated by preparativehigh performance liquid chromatography (CHIRALPAK IC®, 250×20 mm, 5μ;using (A) 0.1% DEA in n-Hexane, (B) EtOH (A:B::60:40) as a mobile phase;Flow rate: 15 mL/min) to obtain 8-(+) (115 mg) as off-white solid.

Analytical Data for 8-(+):

¹H-NMR (400 MHz, CDCl₃): δ 8.76 (s, 1H), 8.62 (s, 1H), 7.84 (d, J=8.0Hz, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.69-7.51 (m, 3H), 7.47 (d, J=7.5 Hz,2H), 7.33-7.27 (m, 2H), 6.96 (d, J=7.5 Hz, 2H), 6.78-6.73 (m, 1H),6.69-6.64 (m, 1H), 5.60 (d, J=14.0 Hz, 1H), 5.16 (s, 2H), 5.12 (d,J=14.0 Hz, 1H).

Chiral HPLC Purity: 99.74% ee R_(t)=18.11 min (CHIRALPAK IC®, 250×4.6mm, 5μ; mobile phase (A) 0.1% DEA in n-hexane, (B) EtOH (A:B::60:40);flow Rate: 1.00 mL/min).

Optical rotation [α]_(D) ²⁰: +27.000 (c=0.1% in MeOH). Mass: m/z 585[M+H]⁺. HPLC: 98.7%.

Example 92-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl) ethynyl) pyridin-2-yl)propan-2-ol (9)

To a stirred solution of 4-bromobenzaldehyde (P) (2.0 g, 10.81 mmol) inDME (20 mL) were added CF₃TMS (1.4 mL, 16.2 mmol) and CsF (1.64 g, 10.81mmol) at 0° C. under inert atmosphere. The resulting reaction mixturewas stirred for 16 h at RT; progress of the reaction was monitored byTLC. The reaction mixture was then quenched with 1N aq. HCl (8 mL) andstirring was continued for another 1 h at RT. The volatiles wereevaporated under reduced pressure; the residue was diluted with water(100 mL) and extracted with DCM (2×100 mL). The combined organic layerwas washed with water (100 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to obtain the crude. The crudecompound was purified by silica gel column chromatography (eluent: 5-6%EtOAc/hexanes) to afford Q (0.65 g, 2.54 mmol, 23.5%) as yellow syrup.¹H NMR (500 MHz, CDCl₃): δ 7.54 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.0 Hz,2H), 5.01-4.98 (m, 1H), 2.87 (bs, OH).

To a stirred solution of Q (0.45 g, 1.76 mmol) in Et₃N (5 mL) were addedTMS-acetylene (0.33 mL, 2.65 mmol), Pd(PPh₃)₂Cl₂ (41 mg, 0.035 mmol) andCuI (11 mg, 0.053 mmol) at RT under inert atmosphere. The resultingreaction mixture was gradually heated up to 75° C. stirred for 16 h;progress of the reaction was monitored by TLC. The reaction mixture wasthen cooled to RT, diluted with water (50 mL) and extracted with Et₂O(2×50 mL). The combined organic layer was washed with brine (50 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toobtain the crude. The crude material was purified by silica gel columnchromatography (eluent: 5% EtOAc/hexane) to afford R (0.4 g, 1.47 mmol,83%) as brown syrup. ¹H NMR (400 MHz, CDCl₃): δ 7.56 (d, J=8.8 Hz, 2H),7.37 (d, J=8.8 Hz, 2H), 5.04-5.01 (m, 1H), 2.68 (bs, OH), 0.26 (s, 9H).

To a stirred solution of compound R (0.4 g, 1.47 mmol) in THF (3 mL) wasadded TBAF (1.5 mL, 1.47 mmol, 1M in THF) drop wise at 0° C. and stirredfor 1 h; progress of the reaction was monitored by TLC. The volatileswere evaporated under reduced pressure to obtain the crude. The crudematerial was purified by silica gel column chromatography (eluent: 5%EtOAc/Hexane) to afford S (0.25 g, 1.25 mmol, 85%) as brown syrup. ¹HNMR (500 MHz, CDCl₃): δ 7.53 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H),5.04-5.02 (m, 1H), 3.11 (s, 1H), 2.62 (bs, OH). To a stirred solution ofS (0.1 g, 0.5 mmol) in Et₂O (6 mL) was added n-BuLi (0.7 mL, 1.1 mmol;1.6 M in hexane) at −78° C. under inert atmosphere. After being stirredfor 45 min, n-Bu₃SnCl (0.27 mL, 1.0 mmol) was added drop wise andstirred for another 10 min at −78° C. The resulting reaction mixture wasallowed to warm to RT and continued stirring for another 2 h; progressof the reaction was monitored by TLC. The reaction was then quenchedwith aqueous NH₄Cl (20 mL) and extracted with EtOAc (2×25 mL). Thecombined organic layers were washed with water (20 mL), brine (20 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford T (0.3 g, crude) as yellow syrup. This was used for the next stepwithout further purification.

To a stirred solution of compound C (10.0 g, 27.62 mmol) in DMF (20 mL)was added 1H-tetrazole (2.85 g, 41.43 mmol) followed by K₂CO₃ (3.81 g,27.62 mmol) at RT. The resulting reaction mixture was gradually heatedto 65° C. and stirred for 16 h; the progress of the reaction wasmonitored by TLC. The reaction was diluted with ice-cold water (250 mL)and extracted with EtOAc (2×250 mL). The combined organic layer waswashed with water (200 mL), brine (200 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to obtain a crude product. Thecrude material was purified by silica gel column chromatography (eluent:40% EtOAc/hexanes) to afford U (5.20 g, 12.03 mmol, 43.5%) as paleyellow solid.

¹H NMR (500 MHz, CDCl₃): δ 8.73 (s, 1H), 8.62 (s, 1H), 7.95 (dd, J=8.0,2.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.31-7.27 (m, 1H), 6.86 (s, OH),6.77-6.73 (m, 1H), 6.70-6.66 (m, 1H), 5.60 (d, J=14.5 Hz, 1H), 5.11 (d,J=14.5 Hz, 1H).

Chiral preparative HPLC method for separation of enantiomers of U(preparation of U (−)).

The enantiomers of U (5.20 g, 12.03 mmol) were separated by normal-phasepreparative high performance liquid chromatography (CHIRALPAK IA, 250×20mm, 5μ; using (A) n-Hexane, (B) EtOH (A:B::90:10) as a mobile phase;Flow rate: 15 mL/min) to obtain U-(−) (2.5 g) as off-white solid.

Analytical Data for U-(−):

Chiral HPLC: 99.46% ee R_(t)=20.05 min (Chiralpak IA, 250×4.6 mm, 5μ;mobile phase (A) n-hexane-(B) Ethanol (A:B:90:10); flow Rate: 1.00mL/min).

Optical rotation [α]_(D) ²⁵: −16.48° (c=0.1% in MeOH).

¹H NMR (500 MHz, CDCl₃): δ 8.73 (s, 1H), 8.62 (s, 1H), 7.95 (dd, J=8.0,2.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.31-7.27 (m, 1H), 6.86 (s, OH),6.77-6.73 (m, 1H), 6.70-6.66 (m, 1H), 5.60 (d, J=14.5 Hz, 1H), 5.11 (d,J=14.5 Hz, 1H). Mass: m/z 430 [M−2]⁻. HPLC: 99.7%.

To a stirred solution of T (0.43 g, crude) in 1,4-dioxane (5 mL) wasadded U-(−) (0.18 g, 0.42 mmol) at RT and purged with argon for 5 min.To the resulting reaction mixture was added Pd(PPh₃)₄ (24 mg, 0.03 mmol)and purged with argon for another 10 min at RT. The resulting reactionmixture was gradually heated up to 90° C. and stirred for 2 h; progressof the reaction was monitored by TLC. The reaction mixture was thencooled to RT; the volatiles were evaporated under reduced pressure toobtain the crude. The crude material was purified by silica gel columnchromatography (eluent: 40% EtOAc/hexane) to afford 9 (90 mg, crude) asbrown solid.

Chiral Preparative HPLC Method for Separation of Enantiomers of U(Preparation of 9 (−)):

The enantiomers of 9 (35 mg) were separated by normal-phase preparativehigh performance liquid chromatography (CHIRALPAK IA, 250×20 mm, 5μ;using (A) 0.1% DEA in n-Hexane, (B) EtOH:MeOH (80:20) (A:B:80:20) as amobile phase; Flow rate: 15 mL/min) to obtain 9 (−) (15 mg) as off-whitesolid.

Analytical Data for 9-(−):

Chiral HPLC: 100% ee R_(t)=19.56 min (Chiralpak IA, 250×4.6 mm, 5μ;mobile phase (A) 0.1% DEA in n-hexane-(B) EtOH: MeOH (80:20)(A:B::80:20); flow Rate: 1.00 mL/min) Optical rotation [α]_(D) ²⁰:+2.16° (c=0.1% in MeOH).

¹H NMR (400 MHz, CDCl₃): δ 8.75 (s, 1H), 8.66 (s, 1H), 7.90 (d, J=8.4Hz, 1H), 7.60-7.51 (m, 5H), 7.34-7.28 (m, 1H), 6.79-6.73 (m, 1H),6.67-6.65 (m, 1H), 5.61 (d, J=14.4 Hz, 1H), 5.13 (d, J=14.4 Hz, 1H),5.09-5.06 (m, 1H), 2.98 (bs, OH). Mass: m/z 552.1 [M+H]⁺. HPLC: 99.5%.

Example 102-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((1-methyl-1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(10)

To a stirred solution of 1H-pyrrole (V) (3.0 g, 44.7 mmol) in THF (100mL) was added n-BuLi (30.7 mL, 49.1 mmol; 1.6M solution in hexane) at−78° C. and maintained for 30 min at the same temperature under argonatmosphere. To the reaction mixture was added triisopropylsilyl chloride(9.56 mL, 44.7 mmol) at −78° C. and the resulting reaction mixture wasallowed to warm to RT and then stirred for additional 30 min. Aftercomplete consumption of the starting material (monitored by TLC), thereaction mixture was quenched with saturated aq. NH₄Cl solution and thenextracted with EtOAc (2×100 mL). The combined organic extracts werewashed with water (100 mL), dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to obtain W (6.5 g, 29.14 mmol, 65%) as acolorless syrup. ¹H NMR (500 MHz, CDCl₃): δ 6.79 (s, 2H), 6.31 (s, 2H),1.52-1.42 (m, 3H), 1.09 (d, J=7.5 Hz, 18H).

To a stirred solution of compound W (3.0 g, 13.45 mmol) and Hg(OAc)₂(4.7 g, 14.84 mmol) in DCM (200 mL) was added a solution of Iodine (3.41g, 13.45 mmol) in DCM (300 mL) drop wise over a period of 45 min at −25°C. and then maintained for 5 h at the same temperature under argonatmosphere. After complete consumption of the starting material(monitored by TLC), the reaction mixture was concentrated under reducedpressure to obtain crude X. The crude material was triturated withhexane (15 mL) and the obtained material (2.1 g) was directly taken forthe next reaction without further purification. ¹H NMR (500 MHz, CDCl₃):δ 6.64 (s, 1H), 6.36 (s, 1H), 6.31 (s, 1H), 1.53-1.25 (m, 3H), 1.09 (d,J=7.5 Hz, 18H).

To a stirred solution of epoxy tin compound G (1.0 g, crude) in1,4-dioxane (20 mL) were added compound X (936 mg, crude) followed byPd(PPh₃)₄ (193 mg, 0.167 mmol) at RT under intert atmosphere. Theresulting solution was purged with argon gas for 15 min. The reactionmixture was slowly heated up to 90° C. and then maintained for 3 h.After complete consumption of the starting material (monitored by TLC),the reaction mixture was cooled to RT and concentrated under reducedpressure to obtain the crude. The crude material was purified by silicagel column chromatography (eluent: 5% EtOAc/hexane) to afford Y (90 mg)as a colorless semi solid. This compound contained some amount of tinimpurities, which was directly taken for the next step without anyfurther purification. LC-MS(ESI): m/z 529 [M+H]⁺ at RT 6.06 min with67.2% purity.

To a stirred solution of compound Y (600 mg, mixture) in THF (20 mL) wasadded TBAF (1.1 mL, 1.13 mmol) at 0° C. under inert atmosphere. Thereaction mixture was allowed to warm to RT and maintained for 30 min.After complete consumption of the starting material (monitored by TLC),the reaction mixture was diluted with water (20 mL) and extracted withEtOAc (2×30 mL).

The combined organic extracts were washed with water (40 mL), brine (40mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto obtain the crude. The crude material was purified by silica gelcolumn chromatography (15-20% EtOAc in Hexane gradient) to affordcompound Z (200 mg, 0.53 mmol) as a pale yellow solid. ¹H NMR (500 MHz,CDCl₃): δ 8.72 (s, 1H), 8.38 (s, NH), 7.78 (dd, J=8.5, 1.5 Hz, 1H), 7.40(d, J=8.5 Hz, 1H), 7.38-7.33 (m, 1H), 7.13 (s, 1H), 6.84-6.71 (m, 3H),6.43 (s, 1H), 3.46 (d, J=5.0 Hz, 1H), 2.97 (d, J=5.0 Hz, 1H). MS (EI):m/z 373 [M+H]⁺.

To a stirred solution of compound Z (100 mg, 0.26 mmol) in ACN (10 mL)was added K₂CO₃ (111 mg, 0.80 mmol) at RT under inert atmosphere. Afterbeing stirred for 30 min, iodomethane (0.1 mL, 1.3 mmol) was added tothe reaction mixture slowly at RT and the resulting reaction mixture washeated up to 80° C. and then stirred for 6 h. After complete consumptionof the starting material (monitored by TLC), the reaction mixture wascooled to RT and concentrated under reduced pressure. The obtainedresidue was dissolved in EtOAc (25 mL), washed with water (20 mL), brine(20 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to obtain the crude. The crude material was purified by silicagel column chromatography (10-15% EtOAc in Hexane gradient) to affordcompound AA (50 mg, 0.12 mmol, 48%) as a brown syrup. ¹H NMR (500 MHz,CDCl₃): δ 8.70 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H),7.36-7.33 (m, 1H), 6.93 (s, 1H), 6.84-6.81 (m, 1H), 6.75-6.71 (m, 1H),6.56 (s, 1H), 6.33 (s, 1H), 3.67 (s, 3H), 3.46 (d, J=5.0 Hz, 1H), 2.97(d, J=5.0 Hz, 1H).

To a stirred solution of compound AA (100 mg, 0.25 mmol) in DMF (5 mL)was added K₂CO₃ (35 mg, 0.25 mmol) followed by 1H-tetrazole (27 mg, 0.38mmol) at RT under inert atmosphere. The reaction mixture was then heatedup to 65° C. and then stirred for 16 h. After complete consumption ofthe starting material (monitored by TLC), the reaction mixture wascooled to RT and concentrated under reduced pressure. The obtainedresidue was dissolved in EtOAc (30 mL), washed with water (20 mL), brine(20 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to obtain the crude. The crude material was purified by silicagel column chromatography (eluent: 30-35% EtOAc in Hexane gradient) toafford 10 (23 mg, 0.05 mmol, 20%) as a colorless solid. ¹H NMR (500 MHz,CDCl₃): δ 8.75 (s, 1H), 8.57 (s, 1H), 7.79 (dd, J=8.5, 1.5 Hz, 1H), 7.49(s, OH), 7.48 (d, J=8.5 Hz, 1H), 7.30-7.27 (m, 1H), 6.92 (s, 1H),6.76-6.72 (m, 1H), 6.66-6.63 (m, 1H), 6.56 (s, 1H), 6.31 (s, 1H), 5.63(d, J=14.0 Hz, 1H), 5.08 (d, J=14.0 Hz, 1H), 3.67 (s, 3H). MS (EI): n/z457 [M+H]⁺. HPLC: 97.17%.

Example 112-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)thiophen-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(11)

To a stirred suspension of copper powder (2.07 g, 33.0 mmol) in DMSO (5mL) was added ethyl bromodifluoroacetate (2.0 mL, 16.52 mmol) at RT andthen stirring was maintained for 1 h under inert atmosphere. To this,compound AB (2.0 g, 8.26 mmol) was added and stirred at RT for 10 h.

After completion of reaction (monitored by TLC), the reaction wasquenched with saturated aqueous NH₄Cl solution (30 mL) and extractedwith DCM (3×50 mL). The combined organic extracts were washed with water(50 mL), brine (50 mL), dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to obtain the crude. The crude material waspurified by silica gel column chromatography (0-2% EtOAc in Hexanegradient) to afford compound AC (0.56 g, 1.96 mmol, 23.7%) as a brownsyrup. ¹H NMR (500 MHz, CDCl₃): δ 7.17 (d, J=4.0 Hz, 1H), 7.02 (d, J=4.0Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H).

To a stirred solution of 1-bromo-2,4-difluorobenzene AC (0.25 ml, 1.96mmol) in Et₂O (10 mL) was added n-BuLi (1.3 mL, 1.96 mmol; 1.6M inhexane) at −78° C. and stirred for 30 min under inert atmosphere. Asolution of ester AC (560 mg, 1.96 mmol) in Et₂O (2 mL) was added to thereaction mixture at −78° C. and stirring was continued for another 2 h.After completion of the reaction (monitored by TLC), the reactionmixture was quenched with saturated NH₄Cl solution (15 mL) and extractedwith EtOAc (3×20 mL). The combined organic extracts were washed withwater (30 mL), brine (30 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to obtain crude. The crude materialwas purified by silica gel column chromatography (15-20% EtOAc in hexanegradient) to afford the ketone AD (400 mg, 1.13 mmol, 57.6%) as a brownsyrup. ¹H NMR (500 MHz, CDCl₃): δ 7.86-7.81 (m, 1H), 7.10 (d, J=4.0 Hz,1H), 7.04 (d, J=4.0 Hz, 1H), 7.01-6.98 (m, 1H), 6.91-6.84 (m, 1H).MS(EI): m/z 354 [M+H]⁺.

To a stirred solution of ketone AD (430 mg, 1.218 mmol) in Et₂O (10 mL)was added freshly prepared diazomethane [prepared by dissolving NMU (627mg, 6.09 mmol) in 1:1 mixture of 10% aq. KOH solution (40 mL) and Et₂O(40 mL) at 0° C. followed by separation and drying of the organic layerusing KOH pellets] at −5° C. and stirred for 2 h. The resulting reactionmixture was allowed to warm to RT and stirring was continued foradditional 3 h. The progress of the reaction was monitored by TLC. Thereaction mixture was concentrated under reduced pressure and theobtained crude material was purified by silica gel column chromatography(20-25% EtOAc in hexane gradient) to afford the epoxide AE (320 mg, 0.87mmol, 71.5%) as a brown syrup. ¹H NMR (500 MHz, CDCl₃): δ 7.36-7.29 (m,1H), 6.98 (d, J=4.0 Hz, 1H), 6.94 (d, J=4.0 Hz, 1H), 6.87-6.76 (m, 2H),3.36 (d, J=5.0 Hz, 1H), 2.98 (d, J=5.0 Hz, 1H). MS(EI): m/z 368 [M]⁺.

To a stirred solution of epoxide AE (320 mg, 0.87 mmol) in DMF (5 mL)was added 1H-tetrazole (92 mg, 1.3 mmol) followed by K₂CO₃ (120 mg, 0.87mmol) at RT under inert atmosphere. The reaction mixture was graduallyheated up to 65° C. and maintained for 8 h. The progress of the reactionwas monitored by TLC. After complete consumption of starting material,the reaction mixture was diluted with ice-cold water (20 mL) and thenextracted with EtOAc (3×30 mL). The combined organic extracts werewashed with water (30 mL), brine (30 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to obtain the crude. The crudematerial was purified by silica gel column chromatography (40-45% EtOAcin Hexane gradient) to afford AF (120 mg, 0.27 mmol, 31.5%) as a brownsolid. ¹H NMR (500 MHz, CDCl₃): δ 8.61 (s, 1H), 7.39-7.35 (m, 1H), 6.93(d, J=4.0 Hz, 1H), 6.83 (d, J=4.0 Hz, 1H), 6.79-6.75 (m, 2H), 5.60 (d,J=14.0 Hz, 1H), 5.00 (d, J=15.0 Hz, 1H), 4.39 (s, OH). MS(EI): m/z 435[M−H]⁻. HPLC: 91.2%.

1-Ethynyl-4-fluorobenzene (22 mg, 0.18 mmol), CuI (2 mg, 0.01 mmol),PPh₃ (3 mg, 0.01 mmol) were added successively to a stirred solution ofAF (50 mg, 0.114 mmol) in Et₃N-DMF (2:1; 6 mL) at RT under inertatmosphere. The resulting mixture was degassed by purging with argon for15 min. To this, Pd(PPh₃)₂Cl₂ (8 mg, 0.01 mmol) was added and againpurged with argon for 15 min. The resulting mixture was then heated to90° C. and maintained for 16 h at the same temperature. After completeconsumption of starting material (monitored by TLC), the reactionmixture was cooled to RT, diluted with water (10 mL) and extracted withEtOAc (3×25 mL). The combined organic extracts were washed with water(30 mL), brine (30 mL), dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to obtain the crude. The crude product waspurified by silica gel column chromatography (40-45% EtOAc in Hexanegradient) to afford 11 (35 mg) with 79% HPLC purity.

Note: The above reaction was conducted in two batches (50 mg×2) and thenpurified. The obtained product (70 mg) as a mixture was further purifiedby preparative HPLC to afford 11 (35 mg, 0.073 mmol, 32%). ¹H NMR (500MHz, CDCl₃): δ 8.64 (s, 1H), 7.50-7.47 (m, 2H), 7.36-7.29 (m, 1H),7.09-7.03 (m, 3H), 6.97 (d, J=5.0 Hz, 1H), 6.80-6.74 (m, 2H), 5.63 (d,J=15.0 Hz, 1H), 5.03 (d, J=15.0 Hz, 1H), 4.41 (s, OH). MS(EI): m/z 475[M−H]⁻. HPLC: 98.43%.

Example 122-(2,4-Difluorophenyl)-1-(6-((3,4-difluorophenyl)ethynyl)pyridazin-3-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(12)

To a stirred solution of compound AG (6.0 g, 31.08 mmol) in THF (20 mL),were added trimethylsilyl acetylene (6 mL, 42.4 mmol), Et₃N (6.0 mL,43.2 mmol) followed by CuI (344 mg, 1.81 mmol) at RT and purged withargon for 10 min. To this mixture, Pd(PPh₃)₂Cl₂ (1.3 g, 1.85 mmol) wasadded at RT and stirring was continued for 16 h under inert atmosphere.After complete consumption of the starting material (monitored by TLC),the reaction mixture was filtered through a pad of celite and washedcelite cake with EtOAc (3×75 mL). The filtrate was washed with water (75mL), brine (75 mL), dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to obtain the crude. The crude material was purified bysilica gel column chromatography (eluent: hexanes) to afford compound AH(5.8 g, 27.61 mmol, 88.8%) as a dark brown liquid.

¹H NMR (500 MHz, CDCl₃): δ 7.28-7.20 (m, 1H), 7.20-7.17 (m, 1H),7.10-7.05 (m, 1H), 0.22 (s, 9H)

To a stirred solution of compound AH (5.8 g, 27.61 mmol) in THF (50 mL)was added TBAF (27 mL, 27.61 mmol; 1M solution in THF) at 0° C. underinert atmosphere and stirred at same temperature for 1 h. After completeconsumption of the starting material (by TLC), volatiles wereconcentrated under reduced pressure; the obtained residue was dilutedwith Et₂O (100 mL), washed with water (100 mL), brine (100 mL), driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to obtainthe crude AI (3.4 g) as a brown liquid. The crude product was used inthe next step without further purification. ¹H NMR (500 MHz, CDCl₃): δ7.31-7.21 (m, 2H), 7.13-7.08 (m, 1H), 3.06 (s, 1H)

To a stirred solution of compound AJ (3.0 g, 12.61 mmol) in THF (30 mL)were added compound AI (2.78 g, crude) followed by CuI (0.12 g, 0.63mmol), Pd(PPh₃)₂Cl₂ (0.44 g, 0.63 mmol) and Et₃N (3 mL) at RT underinert atmosphere and stirred for 16 h. After complete consumption of thestarting material (by TLC), the reaction mixture was filtered through apad of celite and washed the celite cake with EtOAc (3×75 mL). Thefiltrate was washed with water (75 mL), brine (75 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to obtain thecrude. The crude compound was purified by silica gel columnchromatography (eluent: 5% EtOAc/Hexanes) to afford compound AK (1.3 g,4.40 mmol, 35%) as a brown solid. ¹H NMR (500 MHz, CDCl₃): δ 7.67 (d,J=8.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.46-7.42 (m, 1H), 7.39-7.37 (m,1H), 7.22-7.17 (m, 1H).

To a stirred suspension of copper-bronze (3.23 g, 17.62 mmol) in DMSO(20 mL) was added ethyl bromodifluoroacetate (1.13 mL, 8.81 mmol) at RTand stirred for 1 h under inert atmosphere. A solution of compound AK(1.3 g, 4.40 mmol) in DMSO (5 mL) was added to the reaction mixture andstirring was continued for another 16 h at RT. After the consumption ofstarting material (monitored by TLC), the reaction was diluted withaqueous NH₄Cl solution (20 mL), filtered through a pad of celite andwashed celite cake with DCM (3×55 mL). The collected filtrate was washedwith water (30 mL), brine (30 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to obtain the crude. The crudematerial was purified by column chromatography (eluent: 20%EtOAc/Hexanes) to afford ester AL (550 mg, 1.62 mmol, 37%) as a brownsolid. ¹H NMR (500 MHz, CDCl₃): δ 7.88 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.5Hz, 1H), 7.42-7.39 (m, 2H), 7.24-7.20 (m, 1H), 4.43 (q, J=7.0 Hz, 2H),1.36 (t, J=7.0 Hz, 3H) To a stirred solution of1-bromo-2,4-difluorobenzene (0.19 mL, 1.62 mmol) in Et₂O (20 mL) wasadded n-BuLi (1.6 mL, 2.43 mmol; 1.6M in hexane) drop wise at −78° C.and stirred for 30 min. A solution of compound AL (550 mg, 1.62 mmol) inEt₂O (10 mL) was added to the reaction mixture at −78° C. and stirringwas continued for another 5 min. After consumption of the startingmaterial (monitored by TLC), the reaction mixture was quenched withsaturated aqueous NH₄Cl solution (20 mL) and extracted with EtOAc (3×25mL). The combined organic extracts were washed with water (50 mL), brine(50 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to obtain the crude. The crude compound was purified by columnchromatography (eluent: 10% EtOAc/Hexanes) to afford ketone AM (420 mg,1.03 mmol, 64%) as an off white solid. ¹H NMR (500 MHz, CDCl₃): δ8.18-8.14 (m, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H),7.46-7.39 (m, 2H), 7.24-7.18 (m, 1H), 7.05-7.02 (m, 1H), 6.83-6.79 (m,1H).

To a stirred solution of compound AM (420 mg, 1.03 mmol) in Et₂O (10 mL)was added freshly prepared diazomethane [prepared by dissolving NMU (527mg, 5.17 mmol) in 10% aqueous KOH (100 mL) and Et₂O (100 mL) at 0° C.followed by separation and drying of the organic layer using KOHpellets] at 0° C. and stirring was continued for 30 min at 0° C. Theresulting reaction mixture was allowed to warm to RT and stirred for 16h. The progress of the reaction was monitored by TLC. The reactionmixture was concentrated under reduced pressure to obtain the crude. Thecrude material was purified by silica gel column chromatography (eluent:20% EtOAc/Hexanes) to afford compound AN (350 mg) as an off-white solid.¹H-NMR showed all characteristic peaks along with other minorimpurities. This material was directly taken for next reaction withoutfurther purification. ¹H NMR (400 MHz, CDCl₃): δ 8.09 (d, J=8.0 Hz, 1H),7.67 (d, J=8.0 Hz, 1H), 7.45-7.40 (m, 3H), 7.24-7.19 (m, 1H), 6.88-6.85(m, 1H), 6.79-6.76 (m, 1H), 3.51 (d, J=5.0 Hz, 1H), 3.04 (d, J=5.0 Hz,1H).

To a stirred solution of compound AN (300 mg, mixture) in DMF (5 mL)were added 1H-tetrazole (75 mg, 1.07 mmol) followed by K₂CO₃ (99 mg,0.71 mmol) at RT under inert atmosphere. The resulting reaction mixturewas gradually heated up to 65° C. and stirred for 16 h; progress of thereaction was monitored by TLC. The reaction mixture was cooled to RT;diluted with ice-cold water (50 mL) and extracted with EtOAc (2×50 mL).The combined organic layers were washed with water (2×50 mL), brine (50mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto obtain the crude. The crude compound was purified by prep HPLC toafford 12 (25 mg, 0.05 mmol) as a brown solid. ¹H NMR (500 MHz, CD₃OD):δ 8.98 (s, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H),7.64-7.60 (m, 1H), 7.51-7.49 (m, 1H), 7.40-7.35 (m, 1H), 7.17-7.12 (m,1H), 6.98-6.95 (m, 1H), 6.76-6.73 (m, 1H), 5.82 (d, J=14.5 Hz, 1H), 5.25(d, J=14.5 Hz, 1H). MS (ESI): 491 [M+H]⁺. HPLC: 97.19%

Example 134-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)but-3-yn-2-ol(13)

To a stirred solution of alkyne F (800 mg, 2.6 mmol) in Et₂O (50 mL) wasadded n-BuLi (1.63 mL, 2.6 mmol; 1.6M solution in hexane) at −78° C. andmaintained for 30 min at the same temperature. To the resulting reactionmixture, freshly distilled acetaldehyde (0.14 mL, 3.1 mmol) was added at−78° C. After being stirred for 2 h at −78° C., the reaction mixture wasallowed to warm to RT and stirred for additional 2 h. The progress ofthe reaction was monitored by TLC. After complete consumption of thestarting material, the reaction mixture was quenched with saturatedNH₄Cl solution (10 mL) and then extracted with EtOAc (2×50 mL). Thecombined organic extracts were washed with water (50 mL), brine (50 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toobtain the crude. The crude material was purified by silica gel columnchromatography (10-15% EtOAc in hexane gradient) to afford compound AO(600 mg, 1.7 mmol, 65%) as a colorless semi solid. ¹H NMR (500 MHz,CDCl₃): δ 8.68 (s, 1H), 7.75 (dd, J=8.5, 1.5 Hz, 1H), 7.42 (d, J=8.5 Hz,1H), 7.37-7.33 (m, 1H), 6.84-6.81 (m, 1H), 6.75-6.71 (m, 1H), 4.81-4.76(m, 1H), 3.45 (d, J=5.0 Hz, 1H), 2.97 (d, J=5.0 Hz, 1H), 2.04 (s, OH),1.58 (d, J=7.0 Hz, 3H). MS(EI): m/z 353 [M+2]⁺.

To a stirred solution of compound AO (500 mg, 1.4 mmol) in DMF (25 mL)was added K₂CO₃ (196 mg, 1.4 mmol) followed by 1H-tetrazole (150 mg, 2.1mmol) at RT under inert atmosphere. The reaction mixture was then heatedup to 65° C. and stirred for 16 h. After complete consumption of thestarting material (monitored by TLC), the reaction mixture was cooled toRT and concentrated under reduced pressure. The obtained residue wasdissolved in EtOAc (40 mL), washed with water (20 mL), brine (20 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toobtain the crude. The crude material was purified by silica gel columnchromatography (30-35% EtOAc in hexane gradient) to afford 13 (250 mg,0.59 mmol, 41%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 8.74 (s,1H), 8.54 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H),7.30-7.27 (m, 1H), 7.22 (s, OH), 6.77-6.73 (m, 1H), 6.67-6.64 (m, 1H),5.58 (d, J=14.5 Hz, 1H), 5.12 (d, J=14.5 Hz, 1H), 4.79-4.76 (m, 1H),1.93 (s, OH), 1.56 (d, J=7.0 Hz, 3H). MS(EI): m/z 421 [M]⁺. HPLC:98.02%.

Example 142-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoro-1-hydroxyethyl)thiophen-2-yl)ethynyl)pyridin-2-yl)propan-2-ol(14)

To a stirred solution of 5-bromothiophene-2-carboxaldehyde AP (5.0 g,26.1 mmol) in DME (30 mL) was added CsF (3.9 g, 26.1 mmol) at 0° C. andstirred for 10 min under inert atmosphere. CF₃TMS (6.2 mL, 39 mmol) wasadded to the reaction mixture at 0° C. and stirring was continued foranother 18 h at RT. The progress of the reaction was monitored by TLC.The reaction mixture was quenched with 1N HCl solution (20 mL) andextracted with EtOAc (3×100 mL). The combined organic extracts werewashed with water (100 mL), brine (100 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to obtain the crude product. Thecrude material was purified by silica gel column chromatography (eluent:4-5% EtOAc/Hexanes) to afford compound AQ (5.0 g, 19.15 mmol, 73.3%) asa brown oil. ¹H NMR (500 MHz, CDCl₃): δ 6.99 (d, J=4.0 Hz, 1H), 6.93 (d,J=4.0 Hz, 1H), 5.21-5.16 (m, 1H), 3.16 (d, J=4.5 Hz, OH)

To a stirred solution of compound G (1.5 g, crude) in 1,4-dioxane (10mL) was added compound AQ (985 mg, 3.77 mmol) at RT and purged withargon for 20 min. To the resulting reaction mixture was added Pd(PPh₃)₄(288 mg, 0.25 mmol) and further degassed for 15 min at RT. The resultingreaction mixture was gradually heated up to 90° C. and stirred for 5 h;the progress of the reaction was monitored by TLC. The reaction mixturewas cooled to RT, filtered through a pad of celite and the celite cakewas washed with EtOAc (3×30 mL); the filtrate was concentrated underreduced pressure to obtain the crude. The crude material was purified bysilica gel column chromatography (eluent: 12% EtOAc/Hexanes) to affordcompound AR (800 mg) as a colorless liquid. This compound contained someamount of tin impurities, which was directly taken for the next stepwithout any further purification. ¹H NMR (500 MHz, CDCl₃): δ 8.74 (s,1H), 7.83 (d, J=7.5 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.39-7.34 (m, 1H),7.27 (d, J=3.5 Hz, 1H), 7.12 (d, J=3.5 Hz, 1H), 6.85-6.82 (m, 1H),6.76-6.73 (m, 1H), 5.28 (d, J=6.0 Hz, 1H), 3.47 (d, J=5.0 Hz, 1H), 2.98(d, J=5.0 Hz, 1H), 2.91 (s, OH).

To a stirred solution of compound AR (800 mg, crude) in DMF (8 mL) wasadded K₂CO₃ (224 mg, 1.63 mmol) followed by 1H-tetrazole (172 mg, 2.45mmol) at RT under inert atmosphere. The reaction mixture was then heatedup to 65° C. and then stirred for 16 h. After complete consumption ofthe starting material (monitored by TLC), the reaction mixture wascooled to RT and concentrated under reduced pressure. The obtainedresidue was dissolved in EtOAc (50 mL), washed with water (50 mL), brine(50 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to obtain the crude. The crude material was purified by silicagel column chromatography (eluent: 35% EtOAc/Hexanes) to afford 14 (280mg, 0.50 mmol) a pale yellow solid. ¹H NMR (500 MHz, CDCl₃): δ 8.76 (s,1H), 8.63 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H),7.32-7.27 (m, 2H), 7.21 (s, OH), 7.13 (d, J=4.0 Hz, 1H), 6.78-6.74 (m,1H), 6.68-6.65 (m, 1H), 5.61 (d, J=14.0 Hz, 1H), 5.30-5.28 (m, 1H), 5.13(d, J=14.0 Hz, 1H), 3.08 (s, OH). MS(EI): m/z 558 [M+H]⁺. HPLC: 97.43%.

Example 152-(2,4-difluorophenyl)-1-(5-((3,4-difluorophenyl)ethynyl)pyrazin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(15)

To a stirred suspension of copper powder (1.48 g, 23.30 mmol) in DMSO(20 mL) was added ethyl bromodifluoroacetate (1.6 mL, 11.65 mmol) at RTand stirred at RT for 1 h under inert atmosphere. A solution of2-bromo-5-chloropyrazine AS (1.5 g, 7.77 mmol) in DMSO (5 mL) was addedto the reaction mixture and stirring was continued for another 16 h atRT. After complete consumption of the starting material (by TLC), thereaction was diluted with saturated aqueous NH₄Cl solution (100 mL),filtered through a pad of celite and washed celite cake with DCM (3×75mL). The collected filtrate was washed with water (100 mL), brine (50mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto obtain the crude. The crude material was purified by silica gelcolumn chromatography (eluent: 5% EtOAc/Hexane) to afford ester AT (1.0g, 4.23 mmol, 54.5%) as a pale yellow syrup. ¹H NMR (500 MHz, CDCl₃): δ8.78 (s, 1H), 8.62 (s, 1H), 4.38 (q, J=7.0 Hz, 2H), 1.34 (t, J=7.0 Hz,3H).

To a stirred solution of 1-bromo-2,4-difluorobenzene (0.816 g, 4.23mmol) in Et₂O (20 mL) was added n-BuLi (2.64 mL, 4.23 mmol; 1.6M inhexane) drop wise at −78 OC and stirred for 30 min. A solution ofcompound AT (1.0 g, 4.23 mmol) in Et₂O (10 mL) was added to the reactionmixture at −78° C. and stirring was continued for another 2 h. Aftercomplete consumption of the starting material (by TLC), the reactionmixture was quenched with saturated aqueous NH₄Cl solution (50 mL) andextracted with EtOAc (3×50 mL). The combined organic extracts werewashed with water (50 mL) and brine (50 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to obtain the crude. The crudematerial was purified by silica gel column chromatography (eluent: 5%EtOAc/Hexanes) to afford ketone AU (1.0 g, 3.28 mmol, 77.6%) as a paleyellow syrup. ¹H NMR (500 MHz, CDCl₃): δ 8.86 (s, 1H), 8.56 (s, 1H),8.06-8.02 (m, 1H), 7.05-7.01 (m, 1H), 6.88-6.84 (m, 1H).

To a stirred solution of compound AU (1.0 g, 3.28 mmol) in Et₂O (10 mL)was added freshly prepared diazomethane [prepared by dissolving NMU (1.7g, 16.49 mmol) in 10% aqueous KOH (30 mL) and Et₂O (30 mL) at 0° C.followed by separation and drying of the organic layer using KOHpellets] at 0° C. and stirring was continued for 30 min at the sametemperature. The resulting reaction mixture was allowed to warm to RTand stirred for 16 h; progress of the reaction was monitored by TLC. Thereaction mixture was concentrated under reduced pressure to obtain thecrude. The crude material was purified by silica gel columnchromatography (eluent: 5% EtOAc/Hexanes) to afford the epoxide AV (0.8g, 2.51 mmol, 76.5%) as a brown solid. ¹H NMR (500 MHz, CDCl₃): δ 8.62(s, 1H), 8.51 (s, 1H), 7.42-7.37 (m, 1H), 6.90-6.86 (m, 1H), 6.79-6.75(m, 1H), 3.43 (d, J=5.0 Hz, 1H), 3.00 (d, J=5.0 Hz, 1H).

To a stirred solution of compound A1 (400 mg, 1.25 mmol), compound AV(277 mg, 2.0 mmol), Et₃N (0.4 mL, 3.12 mmol) in DMF (10 mL) was addedCuI (12 mg, 0.08 mmol) at RT and then purged with argon for 10 min. Tothis, Pd(PPh₃)₂Cl₂ (44 mg, 0.08 mmol) was added and the resultantmixture was gradually heated up to 80° C. and stirred for 4 h. Aftercomplete consumption of the starting material (monitored by TLC); thereaction mixture was cooled to RT; filtered through a pad of celite andwashed celite cake with EtOAc (4×50 mL). The filtrate was washed withwater (50 mL), brine (50 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to obtain the crude. The crudematerial was purified by silica gel column chromatography (eluent: 10%EtOAc/Hexanes) to afford compound AW (180 mg, 0.42 mmol, 34%) as a brownsolid. ¹H NMR (500 MHz, CDCl₃): δ 8.74 (s, 1H), 8.70 (s, 1H), 7.47-7.39(m, 3H), 7.23-7.18 (m, 1H) 6.89-6.86 (m, 1H), 6.79-6.74 (m, 1H), 3.46(d, J=5.0 Hz, 1H), 3.01 (d, J=5.0 Hz, 1H). MS (EI): m/z 421 [M+H]⁺.

To a stirred solution of compound AW (180 mg, 0.42 mmol) in DMF (5 mL)was added K₂CO₃ (59 mg, 0.42 mmol) followed by 1H-tetrazole (45 mg, 0.64mmol) at RT under inert atmosphere. The reaction mixture graduallyheated to 65° C. and then maintained for 16 h. The progress of thereaction was monitored by TLC. After complete consumption of staringmaterial, the reaction mixture was cooled to RT, diluted with ice-coldwater (50 mL) and extracted with EtOAc (2×50 mL). The combined organicextracts were washed with water (50 mL), brine (50 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to obtain thecrude. The crude material was purified by silica gel columnchromatography (eluent: 35% EtOAc/hexanes) to afford 15 (25 mg, 0.05mmol, 12%) as a brown solid. ¹H NMR (500 MHz, CDCl₃): δ 8.75 (s, 1H),8.71 (s, 1H), 8.62 (s, 1H), 7.46-7.38 (m, 2H), 7.38-7.18 (m, 2H),6.81-6.77 (m, 1H), 6.74-6.71 (m, 1H), 5.64 (d, J=15.0 Hz, 1H), 5.56 (s,OH), 5.17 (d, J=15.0 Hz, 1H). MS (EI): 491[M+H]⁺. HPLC: 92.9%.

Example 162-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoro-1-hydroxyethyl)furan-2-yl)ethynyl)pyridin-2-yl)propan-2-ol (16)

To a stirred solution of 5-bromofuran-2-carbaldehyde AX (250 mg, 1.43mmol) in DME (10 mL) was added CsF (108 mg, 0.71 mmol) at 0° C. andstirred for 10 min under inert atmosphere. CF₃TMS (0.27 mL, 1.71 mmol)was added to the reaction mixture at 0° C. and stirring was continuedart 0° C.-RT for 18 h. The progress of the reaction was monitored byTLC. The reaction mixture was quenched with IN HCl (10 mL) and extractedwith EtOAc (2×50 mL). The combined organic extracts were washed withwater (50 mL), brine (50 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to obtain the crude AY (200 mg),which was directly taken for next reaction without being purified. ¹HNMR (500 MHz, CDCl₃): δ 6.51 (d, J=3.0 Hz, 1H), 6.35 (d, J=3.0 Hz, 1H),5.03-4.99 (m, 1H), 2.78 (bs, OH). To a stirred solution of compound G(500 mg, crude) in 1,4-dioxane (20 mL) was added compound AY (309 mg,crude) at RT and purged with argon for 15 min. To this, Pd(PPh₃)₄ (97mg, 0.08 mmol) was added and further degassed for 15 min. The resultingreaction mixture was gradually heated up to 80° C. and stirred for 3 h;the progress of the reaction was monitored by TLC. The reaction mixturewas cooled to RT, filtered through a pad of celite and washed celitecake with EtOAc (2×50 mL) and the filtrate was concentrated underreduced pressure to obtain the crude. The crude material was purified bysilica gel column chromatography (eluent: 10-12% EtOAc/Hexanes) toafford epoxide AZ (200 mg, mixture) as a colorless oil. ¹H-NMR showedall the characteristic peaks along with little tin-impurity peaks. Theproduct was directly taken for next reaction without furtherpurification. ¹H-NMR (500 MHz, CDCl₃): δ 8.77 (s, 1H), 7.81 (d, J=8.5Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.37-7.32 (m, 1H), 6.79-6.75 (m, 3H),6.60 (d, J=3.5 Hz, 1H), 4.90-5.10 (m, 1H), 3.46 (d, J=5.0 Hz, 1H), 2.98(d, J=5.0 Hz, 1H), 2.75 (d, J=7.0 Hz, OH).

To a stirred solution of epoxide AZ (200 mg, crude) in DMF (10 mL) wasadded 1H-tetrazole (44.5 mg, 0.63 mmol) followed by K₂CO₃ (58.6 mg, 0.42mmol) at RT under inert atmosphere. The resulting reaction mixture wasgradually heated up to 65° C. and stirred for 16 h; progress of thereaction was monitored by TLC. The reaction mixture was diluted withice-cold water (50 mL) and extracted with EtOAc (2×50 mL). The combinedorganic extracts were washed with water (50 mL), brine (50 mL), driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to obtainthe crude. The crude material was purified by silica gel columnchromatography (eluent: 40% EtOAc/hexanes) to afford 16 (20 mg, 0.037mmol) as an off-white solid. ¹H-NMR (500 MHz, CDCl₃): δ 8.75 (s, 1H),8.64 (s, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.32-7.29(m, 1H), 7.10 (s, OH), 6.78-6.65 (m, 3H), 6.60 (d, J=3.5 Hz, 1H), 5.59(d, J=14.5 Hz, 1H), 5.13 (d, J=14.5 Hz, 1H), 5.10-5.07 (m, 1H), 2.78 (d,J=7.0 Hz, OH) Mass: m/z 542 [M+H]⁺. HPLC: 95.59%.

Example 172-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-(3-fluorophenyl)prop-1-yn-1-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(17)

To a stirred solution of trimethylsilylacetylene (1.49 mL, 10.47 mmol)in THF (20 mL) was added n-BuLi (6 mL, 9.67 mmol, 1.6M in Hexane) at 0°C. under inert atmosphere. After being stirred for 1 h,3-fluorobenzaldehyde BA (1.0 g, 8.06 mmol) was added at 0° C. andstirring was continued for additional 2 h. The progress of the reactionwas monitored by TLC. The reaction was quenched with saturated aqueousNH₄Cl solution and extracted with DCM (2×50 mL). The combined organicextracts were washed with water (50 mL), brine (50 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to obtain thecrude. The crude material was purified by silica gel columnchromatography (5-10% EtOAc in Hexane gradient) to afford compound BB(1.1 g, 4.95 mmol, 61.5%) as a yellow syrup. ¹H NMR (400 MHz, CDCl₃): δ7.37-7.28 (m, 3H), 7.04-6.99 (m, 1H), 5.44 (d, J=6.4 Hz, 1H), 2.23 (d,J=6.4 Hz, 1H), 0.21 (s, 9H).

To a stirred solution of compound BB (1.1 g, 4.95 mmol) in MeOH (12 mL)was added K₂CO₃ (1.02 g, 7.43 mmol) at 0° C. under inert atmosphere.After being stirred for 1 h, the progress of the reaction was monitoredby TLC. The reaction was quenched with water (10 mL) and extracted withEt₂O (2×50 mL). The combined organic extracts were washed with water (50mL), brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to obtain the crude BC (600 mg). The crude material wasused for the next step without further purification. ¹H NMR (500 MHz,CDCl₃): δ 7.38-7.26 (m, 3H), 7.05-7.02 (m, 1H), 5.47 (dd, J=4.5, 2.0 Hz,1H), 2.69 (d, J=2.0 Hz, 1H), 2.33 (d, J=4.5 Hz, 1H).

To a stirred solution of compound U (250 mg, 0.578 mmol) in DMF (5 mL)was added compound BC (140 mg, 1.5 eq) and purged with argon gas for 20min. To this, CuI (11 mg, 0.05 mmol), Pd(PPh₃)₄ (34 mg, 0.03 mmol)followed by Et₃N (0.1 mL, 0.69 mmol) were added at RT and then purgedagain with argon gas for 15 min. The resultant mixture was graduallyheated up to 90° C. and maintained for 5 h. After complete consumptionof the starting material (monitored by TLC), the reaction mixture wascooled to RT, diluted with water (20 mL) and extracted with EtOAc (3×40mL). The combined organic extracts were washed with water (50 mL), brine(50 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to obtain crude. The crude product was purified by silica gelcolumn chromatography (40-45% EtOAc in Hexane gradient) to affordcompound BD (180 mg, 0.35 mmol, 62%) as a pale yellow syrup. ¹H NMR (500MHz, CDCl₃): δ 8.74 (s, 1H), 8.58 (s, 1H), 7.85 (d, J=8.0 Hz, 1H),7.67-7.64 (m, 1H), 7.54-7.28 (m, 4H) 7.16 (s, OH), 7.08-7.04 (m, 1H),6.78-6.72 (m, 1H), 6.68-6.63 (m, 1H), 5.71 (d, J=5.2 Hz, 1H), 5.59 (d,J=14.5 Hz, 1H), 5.12 (d, J=14.5 Hz, 1H), 2.74 (d, J=5.2 Hz, 1H). MS(EI):m/z 502 [M+H]⁺.

To a stirred solution of compound BD (110 mg, 0.22 mmol) in ACN (10 mL)were added Et₃SiH (0.052 mL, 0.33 mmol) followed by BF₃.Et₂O (0.04 mL,0.33 mmol) at 0° C. under inert atmosphere and maintained for 5 h at thesame temperature. The progress of the reaction was monitored by TLC. Thereaction was quenched with ice-cold water (10 mL) and extracted withEtOAc (2×30 mL). The combined organic extracts were washed with water(40 mL), brine (40 mL), dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to obtain the crude. The crude product waspurified by silica gel column chromatography (eluent with 40-45%EtOAc/hexanes 25-30% EtOAc in hexane gradient) to afford 17 (8.0 mg) asan off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.76 (s, 1H), 8.48 (s,1H), 7.73 (d, J=7.2 Hz, 1H), 7.48 (d, J=7.2 Hz, 1H), 7.38-7.24 (m, 2H),7.14-7.09 (m, 1H), 7.02-6.92 (m, 2H), 6.78-6.72 (m, 1H), 6.67-6.62 (m,1H), 6.41 (s, OH), 5.60 (d, J=14.5 Hz, 1H), 5.09 (d, J=14.5 Hz, 1H),3.53 (s, 2H). HPLC: 79.36%. LC-MS (ESI): m/z 488 at RT 4.01 min with 88%purity.

Example 182-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-(4-fluorophenoxy)prop-1-yn-1-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(18)

To a stirred solution of 4-fluorophenol (1.0 g, 8.9 mmol) in DMF (25 mL)was added K₂CO₃ (1.84 g, 13.3 mmol) followed by a drop wise addition ofpropargyl bromide (1.1 mL, 9.8 mmol; 80 wt. % in toluene) at 0° C. underinert atmosphere. The resulting reaction mixture was allowed to warm toRT and then stirred for 8 h; progress of the reaction was monitored byTLC. The reaction mixture was quenched with ice-cold water (40 mL) andextracted with EtOAc (2×40 mL). The combined organic extracts werewashed with water (40 mL), brine (40 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to obtain the crude. The crudematerial was purified by silica gel column chromatography (0-5% EtOAc inhexane gradient) to afford compound BE (0.6 g, 4.0 mmol, 45%) as acolorless syrup. ¹H NMR (500 MHz, CDCl₃): δ 7.00-6.91 (m, 4H), 4.65 (d,J=2.5 Hz, 2H), 2.51 (t, J=2.5 Hz, 1H). MS(EI): m/z 151 [M+H]⁺. Astirring mixture of compound U (50 mg, 0.11 mmol), compound BE (28 mg,0.18 mmol), Pd(dppf)Cl₂CH₂Cl₂ complex (8.1 mg, 0.011 mmol),triphenylphosphine (3.0 mg, 0.011 mmol) and CuI (2.2 mg, 0.011 mmol) inEt₃N-DMF (2:1; 6 mL) was degassed by purging with argon for 15 min. Theresulting reaction mixture was slowly heated up to 90° C. and stirringwas continued for 8 h. After complete consumption of the startingmaterial (by TLC), the reaction mixture was cooled to RT, filteredthrough a pad of celite and washed celite cake with EtOAc (3×20 mL).

The filtrate was diluted with water (40 mL) and extracted with EtOAc(2×30 mL). The combined organic extracts were washed with water (30 mL),brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to obtain the crude. The crude material was purified bysilica gel column chromatography (25-30% EtOAc in hexane gradient) toafford 18 (25 mg, 0.049 mmol, 45%) as a brown semi solid. ¹H NMR (500MHz, CDCl₃): δ 8.73 (s, 1H), 8.54 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.51(d, J=8.0 Hz, 1H), 7.30-7.28 (m, 1H), 7.14 (s, OH), 7.03-6.99 (m, 2H),6.96-6.93 (m, 2H), 6.76-6.73 (m, 1H), 6.67-6.64 (m, 1H), 5.58 (d, J=14.0Hz, 1H), 5.11 (d, J=14.0 Hz, 1H), 4.89 (s, 2H). MS(EI): m/z 502 [M+H]⁺.HPLC: 97.55%.

Example 192-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((1-(4-fluorophenyl)piperidin-4-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(19)

To a suspension of piperidin-4-ylmethanol (750 mg, 6.51 mmol) in DCM (20mL) were added 4-fluorophenylboronic acid BF (794 mg, 6.51 mmol),Cu(OAc)₂ (1.18 g, 6.51 mmol), pyridine (2.6 mL, 32.55 mmol), powdered 4A molecular sieves and the reaction was stirred at RT for 16 h underoxygen atmosphere. After consumption of the starting material (monitoredby TLC), the reaction mixture was filtered through a pad of celite andwashed celite cake with DCM (2×100 mL). The filtrate was washed withwater (50 mL), brine (50 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to obtain the crude. The crudematerial was purified by silica gel column chromatography (eluent: 40%EtOAc/hexanes) to afford compound BG (500 mg, mixture) as a colorlessthick syrup. This material was taken for next reaction without furtherpurification.

To a stirred solution of oxalyl chloride (0.42 mL, 4.78 mmol) in DCM (50mL) was cooled to −78° C., and DMSO (0.74 mL, 9.47 mmol) was added dropwise under nitrogen atmosphere. After stirring for 15 min, a solution ofcompound BG (500 mg, crude) in DCM (10 mL) was added slowly at −78° C.and then maintained at same temperature for 15 min. To this, Et₃N (1.25mL, 9.47 mmol) was added and stirring was continued at −78° C. foranother 30 min. The resulting mixture was allowed to warm to RT;progress of the reaction was monitored by TLC. The reaction mixture wasdiluted with water (50 mL) and extracted with DCM (2×50 mL). Thecombined organic extracts were washed with saturated aqueous Na₂CO₃solution (50 mL), water (50 mL), brine (30 mL), dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to obtain the crude BH(500 mg). The crude material was used in next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃): δ 9.71 (s, 1H), 6.98-6.91 (m,4H), 3.50-3.45 (m, 2H), 2.84-2.78 (m, 2H), 2.39-2.36 (m, 1H), 2.07-2.04(m, 2H), 1.87-1.77 (m, 2H).

To a stirred solution of compound BH (500 mg, crude) in MeOH (15 mL) wasadded K₂CO₃ (833 mg, 6.03 mmol) followed by Bestmann reagent (695 mg,3.62 mmol) at RT under inert atmosphere. The reaction mixture wasstirred at RT for 30 min. After completion of the reaction (by TLC), thevolatiles were removed under reduced pressure to obtain the crude. Thecrude material was purified by silica gel column chromatography (eluent:10% EtOAc/Hexanes) to afford compound BI (320 mg, 1.58 mmol) as a whitesolid. ¹H NMR (400 MHz, CDCl₃): δ 6.94-6.87 (m, 4H), 3.38-3.33 (m, 2H),2.92-2.86 (m, 2H), 2.57-2.53 (m, 1H), 2.10 (s, 1H), 2.00-1.96 (m, 2H),1.85-1.79 (m, 2H). MS (EI): m/z 204 [M+H]⁺.

To a stirred solution of compound BJ (300 mg, crude) in DCM (20 mL) wasadded Et₃N (0.28 ml, 1.20 mmol) followed by Tf₂O (0.24 ml, 1.46 mmol) at0° C. and stirred for 20 min; progress of the reaction was monitored byTLC. The reaction mixture was quenched with ice-cold water (20 mL) andextracted with DCM (2×50 mL). The combined organic extracts were washedwith water (50 mL), brine (50 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to obtain the crude BK (360 mg,crude). The crude material was used in next step without furtherpurification.

To a stirred solution of compound BK (150 mg, crude), compound BI (84.3mg, 0.417 mmol), Et₃N (0.15 mL, 0.62 mmol) in DMF (10 mL) were added CuI(3.3 mg, 0.017 mmol), and Pd(PPh₃)₂Cl₂ (24.4 mg, 0.034 mmol) under inertatmosphere. The reaction mixture was gradually heated up to 120° C.under Microwave for 20 min. After complete consumption of the startingmaterial (by TLC), the reaction mixture was allowed to cool to RT;filtered through a pad of celite and washed celite cake with EtOAc (4×25mL). The filtrate was washed with water (40 mL), dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to obtain the crude. Thecrude material was purified by silica gel column chromatography (eluent:10% EtOAc/Hexanes) to afford compound BL (200 mg, crude) as apale-yellow solid.

To a stirred solution of compound BL (200 mg, crude) in DMF (10 mL) wasadded 1H-tetrazole (43.4 mg, 0.619 mmol) followed by K₂CO₃ (57 mg, 0.413mmol) at RT under inert atmosphere. The resulting reaction mixture wasgradually heated up to 65° C. and stirred for 16 h. The progress of thereaction was monitored by TLC. The reaction mixture was diluted withice-cold water (50 mL) and extracted with EtOAc (2×50 mL). The combinedorganic extracts were washed with water (40 mL), brine (40 mL), driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to obtainthe crude. The crude material was purified by silica gel columnchromatography (eluent: 40% EtOAc/hexanes) to afford 19 (60 mg, 0.108mmol) as a light-yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 8.75 (s, 1H),8.52 (s, 1H), 7.77 (dd, J=8.4, 2.0 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.49(s, OH), 7.32-7.27 (m, 1H), 6.99-6.85 (m, 4H), 6.81-6.72 (m, 1H),6.70-6.60 (m, 1H), 5.59 (d, J=14.4 Hz, 1H), 5.10 (d, J=14.4 Hz, 1H),3.42-3.36 (m, 2H), 2.97-2.91 (m, 2H), 2.81-2.76 (m, 1H), 2.06-2.04 (m,2H), 1.93-1.87 (m, 2H). MS (ESI): m/z 555 [M+H]⁺. HPLC: 97.52%.

Example 201-(5-((4-((4-Cyanobenzyl)oxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-yl dihydrogen phosphate (20)

To a stirred suspension of 8(+) (400 mg, 0.686 mmol) and 1H-tetrazole(236 mg, 3.43 mmol) in DCM (25 mL) was added a solution of diallyl-N,N-diisopropylphosphoramidite (0.72 mL, 2.74 mmol) in DCM (5 mL) at RTand stirred for 2 h. A solution of mCPBA (472 mg, 2.74 mmol) in DCM (5mL) was added slowly at −5° C. and stirred for 1 h. After completeconsumption of the starting material, the reaction mixture was dilutedwith DCM (50 mL), washed with 5% aqueous Na₂S₂O₅ (2×40 mL), 10% aqueousNaHCO₃ (2×40 mL), brine (50 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to obtain the crude. The residue waspurified by mass based preparative HPLC to afford compound BM (250 mg,0.336 mmol, 49%) as a colorless semi-solid. ¹H NMR (500 MHz, CDCl₃): δ9.10 (s, 1H), 8.75 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz,2H), 7.56-7.50 (m, 4H), 7.46-7.42 (m, 1H), 7.17 (d, J=8.0 Hz, 1H), 6.96(d, J=8.0 Hz, 2H), 6.83-6.80 (m, 1H), 6.66-6.62 (m, 1H), 6.19 (d, J=16.0Hz, 1H), 6.02-5.97 (m, 1H), 5.91 (d, J=16.0 Hz, 1H), 5.85-5.79 (m, 1H),5.44 (d, J=17.0 Hz, 1H), 5.33-5.22 (m, 3H), 5.16 (s, 2H), 4.74 (d, J=4.0Hz, 2H), 4.49-4.39 (m, 2H). HPLC: 98.46%.

To a stirred solution of compound BM (220 mg, 0.295 mmol) in THF (10 mL)were added TPP (58 mg, 0.221 mmol) followed by Pd(PPh₃)₄ (27 mg, 0.023mmol), Et₃N (0.08 mL, 0.59 mmol) and 1M Acetic acid solution (1.47 mL,1.47 mmol) at 0° C. The resulting mixture was stirred at RT for 16 h;progress of the reaction was monitored by TLC. The reaction mixture wasfiltered through a pad of celite and washed the celite cake with DCM(3×30 mL) and EtOH (3×10 mL). The filtrate was concentrated underreduced pressure to obtain the crude. The crude material was purified bymass based preparative HPLC to afford 20 (70 mg, 0.105 mmol, 35.60%) asa white solid. ¹H NMR (400 MHz, CD₃OD): δ 9.33 (s, 1H), 8.70 (s, 1H),7.92 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H),7.51 (d, J=8.0 Hz, 2H), 7.45-7.39 (m, 1H), 7.34-7.27 (m, 1H), 7.05 (d,J=8.0 Hz, 2H), 6.95-6.89 (m, 1H), 6.83-6.78 (m, 1H), 6.21 (d, J=15.2 Hz,1H), 5.94 (d, J=15.2 Hz, 1H), 5.21 (s, 2H). ³¹P NMR (500 MHz, CD₃OD): δ−6.98 (s). MS (ESI): m/z 665 [M]⁺. HPLC: 97.83%.

Example 1442-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-yl2-aminoacetate hydrochloride (144)

To a stirred solution of 3 (+) (25 mg, 0.053 mmol) in dry THF (3 mL) wasadded NaH (5 mg, 0.21 mmol) at 0° C. and stirred at 0° C. for 2 h underinert atmosphere. A solution of N-Boc-Gly-OSu (28.8 mg, 0.10 mmol) indry THF (2 mL) was added to the reaction mixture at 0° C. and thestirring was continued at same temperature for another 10 h. Theprogress of the reaction was monitored by TLC. The reaction was quenchedwith ice-cold water (10 mL) and then extracted with EtOAc (2×15 mL). Thecombined organic layers were washed with water (10 mL), brine (10 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toobtain the crude product.

Note: The reaction was conducted in 2×25 mg batches and the obtainedcrude product was combined and purified by preparative TLC to afford BN(12 mg, 0.019 mmol, 18%) as pale yellow semi-solid. ¹H NMR (500 MHz,CDCl₃): δ 9.27 (s, 1H), 8.82 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.57-7.54(m, 2H), 7.40-7.39 (m, 1H), 7.11-7.08 (m, 2H), 6.99 (d, J=8.0 Hz, 1H),6.93-6.91 (m, 1H), 6.67-6.63 (m, 1H), 6.05 (d, J=15.0 Hz, 1H), 5.68 (d.J=15.0 Hz, 1H), 5.09 (bs, 1H), 4.19-4.14 (m, 1H), 3.97-3.93 (m, 1H),1.45 (s, 9H). MS (ESI): m/z 629 [M+H]⁺.

To a stirred solution of compound BN (18 mg, 0.028 mmol) in 1,4-dioxane(1 mL) was added 4M HCl solution in 1,4-dioxane (0.5 mL) drop-wise at RTand maintained for 2 h. The progress of the reaction was monitored byTLC. The volatiles were evaporated under reduced pressure. The obtainedcrude was triturated with diethyl ether (3×3 mL) to afford 144 (10 mg,0.017 mmol, 62%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.66 (s, 1H), 8.82 (s, 1H), 8.59 (bs, 3H), 8.03 (d, J=7.6 Hz, 1H),7.69-7.67 (m, 2H), 7.44-7.42 (m, 1H), 7.34-7.30 (m, 4H), 7.12-7.10 (m,1H), 6.15 (d, J=15.6 Hz, 1H), 5.56 (d, J=15.6 Hz, 1H), 4.13 (d, J=17.6Hz, 1H), 3.90 (d, J=17.6 Hz, 1H). MS (ESI): m/z 529 [(M−HCl)+H]⁺. HPLC:97.9%.

Example 145(2S)-2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-yl2,6-diaminohexanoate dihydrochloride (145)

¹H NMR (400 MHz, DMSO-d₆): δ 9.69 (s, 1H), 8.86 (s, 1H), 8.73 (bs, 3H),8.07 (d, J=8.0 Hz, 1H), 7.97 (bs, 3H), 7.71-7.69 (m, 3H), 7.33-7.21 (m,4H), 7.18-7.12 (m, 1H), 6.15 (d, J=15.6 Hz, 1H), 5.63 (d, J=15.6 Hz,1H), 4.25-4.20 (m, 1H), 2.76-2.72 (m, 2H), 1.90-1.83 (m, 2H), 1.61-1.22(m, 4H). MS (ESI): m/z 600 [(M−2HCl)+H]⁺. HPLC: 96.5%.

Examples 21-166 were prepared essentially according to the abovesynthetic procedures. The following table contains compound informationand analytical data for Examples 1-166.

Ex- am- MS Stereo- ple (ESI) chem./ Num- HPLC (M + Optical ber HPLCMethod (RT) H) Rotation Structure  1 Method A: Column, Type, Size:Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ) Mobile Phase: Solvent A:Acetonitrile Solvent B: 0.025% TFA (Aq) Flow Rate: 0.50 mL/min 2.808 454Racemic

 2 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.005 488 Racemic

 3 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.797 472 Racemic

 3 (+) Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.700 472 (+) 28.7

Method B 17.397 Column, Type, Size: ChiralPak IC, 250 × 4.6 mm, 5 μMobile Phase A: n- Hexane Mobile Phase B: IPA A: B:: 50:50 Flow Rate:1.0 mL/min  4 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1mm, 1.7 μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA(Aq) Flow Rate: 0.50 mL/min 2.813 490 Racemic

 5 Method C Column, Type, Size: Acquity UPLC BEH C-18 (2.1 × 50 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.918 522 Racemic

 6 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm. 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.69 611.5 Racemic

 6 (+) Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.725 611 (+) 19.76

Method J 20.224 Column, Type, Size: ChiralPak IA, 250 × 4.6 mm, 5 μMobile Phase A: n- Hexane Mobile Phase B: Ethanol A: B:: 75:25 FlowRate: 1.0 mL/min  7 Method A Column, Type, Size: Acquity BEH C-18 (50 ×2.1 mm, 1.7 μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025%TFA (Aq) Flow Rate: 0.50 mL/min 2.95 603.4 Racemic

 7 (+) Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.022 603 (+) 23.12

Method G 28.550 Column, Type, Size: ChiralPak IC, 250 × 4.6 mm, 5 μmMobile Phase A: 0.1% TEA in n-Hexane Mobile Phase B: Ethanol A: B::70:30 Flow Rate: 1.0 mL/min  8 Method A Column, Type, Size: Acquity BEHC-18 (50 × 2.1 mm, 1.7 μ) Mobile Phase: Solvent A: Acetonitrile SolventB: 0.025% TFA (Aq) Flow Rate: 0.50 mL/min 2.919 585 Racemic

 8 (+) Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.990 585 (+) 29.0

Method L 16.681 Column, Type, Size: ChiralPak IC, 250 × 4.6 mm, 5 μmMobile Phase A: 0.1% DEA in n-Hexane Mobile Phase B: Ethanol A: B::60:40 Flow Rate: 1.0 mL/min  9 Method A Column, Type, Size: Acquity BEHC-18 (50 × 2.1 mm, 1.7 μ) Mobile Phase: Solvent A: Acetonitrile SolventB: 0.025% TFA (Aq) Flow Rate: 0.50 mL/min 2.60 552 Racemic

 9 (−) Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.604 552 (−) 2.160

Method K 19.563 Column, Type, Size: ChiralPak IA, 250 × 4.6mm, 5 μMobile Phase A: 0.1% DFA in n-Hexane Mobile Phase B: Methanol A: B::80:20 Flow Rate: 1.0 mL/min  10 Method A Column, Type, Size: Acquity BEHC-18 (50 × 2.1 mm, 1.7 μ) Mobile Phase: Solvent A: Acetonitrile SolventB: 0.025% TFA (Aq) Flow Rate: 0.50 mL/min 2.525 457 Racemic

 11 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.997 475 (M − H)⁻ Racemic

 12 Method F Column, Type, Size: Eclipse XDB C-18 (150 × 4.63 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 5 mM NH₄OAC Flow Rate: 1.0 mL/min10.567 497 Racemic

 13 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.056 420 (M − H)⁻ Racemic

 14 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.626 558 Racemic

 15 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.732 491 Racemic

 16 Method C Column, Type, Size: Acquity UPLC BEH C-18 (2.1 × 50 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.474 542 Racemic

 17 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.830 486 Racemic

 18 Method F Column, Type, Size: Eclipse XDB C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 5 mM NH₄OAC Flow Rate: 1.0 mL/min8.753 502 Racemic

 19 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.426 555 Racemic

 20 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.574 509 Racemic

 21 Method C Column, Type, Size: Acquity UPLC BEH C-18 (2.1 × 50 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.931 488 Racemic

 22 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.015 540 Racemic

 23 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.401 428 Racemic

 24 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.754 472 Racemic

 25 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.788 472 Racemic

 26 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.751 504 Racemic

 27 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.910 486 Racemic

 28 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.336 473 Racemic

 29 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.013 494 Racemic

 30 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.002 528 Racemic

 31 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.480 491 Racemic

 32 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.401 473 Racemic

 33 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.508 473 Racemic

 34 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.007 538 Racemic

 35 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.777 502 Racemic

 36 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.739 490 Racemic

 37 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.820 490 Racemic

 38 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.896 474 Racemic

 39 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.908 518 Racemic

 40 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.799 520 Racemic

 41 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.165 554 Racemic

 42 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.015 506 Racemic

 43 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.939 489 Racemic

 44 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.995 522 Racemic

 45 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.8020 472 Racemic

 46 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.829 472 Racemic

 47 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.565 496 Racemic

 48 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.726 472 Racemic

 49 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.538 473 Racemic

 50 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.309 484 Racemic

 51 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.751 498 Racemic

 52 Method C Column, Type, Size: Acquity UPLC BEH C-18 (2.1 × 50 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.300 476 Racemic

 53 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.040 539 Racemic

 54 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.790 510 Racemic

 55 Method D Column, Type, Size: X-Terra RP-18 (50 × 4.6 mm, 5 μm)Mobile Phase A: ACN: THE (80:20) Mobile Phase B: 0.1% TFA in water FlowRate: 1.0 mL/min 6.429 556 Racemic

 56 Method E Column, Type, Size: Eclipse XDB C-18 (150 × 4.6 mm, 5.0 μm)Mobile Phase A: ACN Mobile Phase B: 0.1% Aq TFA Flow Rate: 1.0 mL/min11.270 525 Racemic

 57 Method A Column, Type, Size: Acquily BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.371 490 Racemic

 58 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.731 460 Racemic

 59 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.613 501 Racemic

 60 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.55 483 Racemic

 60 (+) Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.647 483 (+) 51.72

Method G 10.965 Column, Type, Size: ChiralPak IC, 250 × 4.6 mm, 5 μMobile Phase A: 0.1% TEA in n-Hexane Mobile Phase B: Ethanol A: B::70:30 Flow Rate: 1.0 mL/min  61 Method A Column, Type, Size: Acquity BEHC-18 (50 × 2.1 mm, 1.7 μ) Mobile Phase: Solvent A: Acetonitrile SolventB: 0.025% TFA (Aq) Flow Rate: 0.50 mL/min 3.017 493 (M − H)⁻ Racemic

 62 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.714 497 Racemic

 63 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.373 441 (M − H)⁻ Racemic

 64 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.821 522 Racemic

 65 Method C Column, Type, Size: Acquity UPLC BEH C-18 (2.1 × 50 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.770 486 Racemic

 66 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.656 493 Racemic

 67 Method C Column, Type, Size: Acquity UPLC BEH C-18 (2.1 × 50 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.708 490 Racemic

 68 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.332 497 Racemic

 69 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.560 479 Racemic

 70 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.740 479 Racemic

 71 Method H Column, Type, Size: Luna C-18 (150 × 2.0 mm, 5.0 μm) MobilePhase A: ACN Mobile Phase B: 0.1% TFA in water Flow Rate: 1.0 mL/min2.840 479 Racemic

 72 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate 0.50 mL/min 2.873 521 (M − H)⁻ Racemic

 73 Method A Column, Type, Size: Acquity BFH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.681 495 (M − H)⁻ Racemic

 74 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.699 497 Racemic

 75 Method C Column, Type, Size: Acquity UPLC BEH C-18 (2.1 × 50 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.597 497 Racemic

 76 Method E Column, Type, Size: Eclipse XDB C-18 (150 × 4.6 mm, 5.0 μm)Mobile Phase A: ACN Mobile Phase B: 0.1% Aq TFA Flow Rate: 1.0 mL/min8.55 494 Racemic

 77 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.87 542 Racemic

 77 (+) Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.904 542 (+) 33.24

Method I 13.045 Column, Type, Size: ChiralPak IC, 250 × 4.6 mm, 5 μMobile Phase A: n- Hexane Mobile Phase B: Ethanol A: B:: 80:20 FlowRate: 1.0 mL/min  78 Method A Column, Type, Size: Acquity BEH C-18 (50 ×2.1 mm, 1.7 μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025%TFA (Aq) Flow Rate: 0.50 mL/min 2.382 469 Racemic

 79 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.763 563 (M − H)⁻ Racemic

 80 Method F Column, Type, Size: Eclipse XDB C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 5 mM NH₄OAC Flow Rate: 1.0 mL/min8.760 551 Racemic

 81 Method F Column, Type, Size: Eclipse XDB C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 5 mM NH₄OAC Flow Rate: 1.0 mL/min7.960 470 Racemic

 82 Method C Column, Type, Size: Acquity UPLC BEH C-18 (2.1 × 50 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.094 495 (M − H)⁻ Racemic

 83 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.536 487 Racemic

 84 Method F Column, Type, Size: Eclipse XDB C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 5 mM NH₄OAC Flow Rate: 1.0 mL/min7.833 511 Racemic

 85 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.797 520 Racemic

 86 Method C Column, Type, Size: Acquity UPLC BEH C-18 (2.1 × 50 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.876 550 (M − H⁾⁻ Racemic

 87 Method C Column, Type, Size: Acquity UPLC BEH C-18 (2.1 × 50 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.591 493 Racemic

 88 Method C Column, Type, Size: Acquity UPLC BEH C-18 (2.1 × 50 mm, 1.7μ) Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.923 577 Racemic

 89 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.857 492 (M − H)⁻ Racemic

 90 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.910 536 Racemic

 91 Method A Column, Type, Size: Acquily BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.555 579 Racemic

 92 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.451 551 Racemic

 93 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.096 578 Racemic

 94 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.568 585 Racemic

 95 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.591 583 Racemic

 96 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.682 557 Racemic

 97 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.910 552 Racemic

 98 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.571 579 Racemic

 99 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.792 454 Racemic

100 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.932 585 Racemic

101 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.236 644 Racemic

102 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.987 603 Racemic

103 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.924 603 Racemic

104 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.283 644 Racemic

105 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.128 596 Racemic

106 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.123 596 Racemic

107 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.252 594 Racemic

108 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.264 612 Racemic

109 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.605 617 Racemic

110 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.781 586 Racemic

111 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.749 567 Racemic

112 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.002 603 Racemic

113 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.129 596 Racemic

114 Method F Column, Type, Size: Eclipse XDB C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 5 mM NH₄OAC Flow Rate: 1.0 mL/min11.687 518 Racemic

115 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TEA (Aq) FlowRate: 0.50 mL/min 2.685 527 Racemic

116 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TEA (Aq) FlowRate: 0.50 mL/min 2.656 527 Racemic

117 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TEA (Aq) FlowRate: 0.50 mL/min 2.925 536 Racemic

118 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.913 534 Racemic

119 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.711 611 Racemic

120 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.674 618 Racemic

121 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.624 616 (M − H)⁻ Racemic

122 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.831 661 Racemic

123 Method A Column, Type, Size: Acquily BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.414 573 Racemic

124 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.509 557 Racemic

125 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.532 671 Racemic

126 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.243 603 Racemic

127 Method A Column, Type, Size: Acquily BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.198 603 Racemic

128 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 1.893 461 Racemic

129 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.936 619 Racemic

130 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.974 602 Racemic

131 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.943 603 Racemic

132 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.335 619 Racemic

133 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.224 619 Racemic

134 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.674 635 Racemic

135 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.811 649 (M − H)⁻ Racemic

136 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.906 585 Racemic

137 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.022 601 Racemic

138 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 3.251 601 Racemic

139 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.828 586 Racemic

140 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.447 665 (M)⁺ —

141 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.752 611 Racemic

142 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.979 585 Racemic

143 Method A Column, Type, Size: Acquily BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.990 603 Racemic

144 Method A Column, Type, Size: Acquity BEH C-18 (50 × 2.1 mm, 1.7 μ)Mobile Phase: Solvent A: Acetonitrile Solvent B: 0.025% TFA (Aq) FlowRate: 0.50 mL/min 2.234 529 (+)

145 Method F Column, Type, Size: Eclipse XDB C-18 (150 × 4.63 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 5 mM NH₄OAC Flow Rate: 1.0 mL/min8.670 600 (+)

146 Method M Column, Type, Size; Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min13.20 613 Racemic

147 Method M Column, Type, Size; Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACM Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min19.90 636 Racemic

148 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACM Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min12.30 574 Racemic

149 Method M Column, Type, Size: Sunfire C-S8 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min16.90 588 Racemic

150 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min7.60 610 Racemic

(+)− Method N 20.669 610 [a]23/D = See above 150 Column, Type, Size:+12.0° (c Chiralpak IA (250 × 1.0 10 mm, 5 μm) MeOH) Mobile Phase A: 15%EtOH Mobile Phase B: 30% IPA Mobile Phase C: 55% hexanes Flow Rate: 1.0mL/min 151 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5μm) Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0mL/min 21.20 628 Racemic

152 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min5.90 603 Racemic

153 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min6.30 603 Racemic

154 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min6.30 626 Racemic

155 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min5.30 585 Racemic

156 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min12.50 594 Racemic

157 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min19.20 636 Racemic

158 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min15.2 627

159 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min12.0 578 Racemic

160 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min14.6 596 Racemic

161 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min20.1 610 Racemic

162 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min16.2 601 Racemic

163 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min12.9 591 Racemic

164 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min12.5 603 Racemic

165 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min38.0 613 Racemic

166 Method M Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm)Mobile Phase A: ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min13.9 585 Racemic

Method Specifications

Method A: Method B: Column, Type, Size: Column, Type, Size: Acquity BEHC-18 (50 × 2.1 mm, 1.7μ) ChiralPak IC, 250 × 4.6 mm, 5μ Mobile Phase:Mobile Phase A: n-Hexane Solvent A: Acetonitrile Mobile Phase B: IPASolvent B: 0.025% TFA (Aq) A:B:: 50:50 Flow Rate: 0.50 mL/min Flow Rate:1.0 mL/min Method C: Method D: Column, Type, Size: Column, Type, Size:Acquity UPLC BEH C-18 (2.1 × 50 mm, 1.7μ) X-Terra RP-18 (50 × 4.6 mm, 5μm) Mobile Phase: Mobile Phase A: ACN:THF (80:20) Solvent A:Acetonitrile Mobile Phase B: 0.1% TFA in water Flow Rate: 1.0 mL/minMethod E: Method F: Column, Type, Size: Column, Type, Size: Eclipse XDBC-18 (150 × 4.6 mm, 5.0 μm) Eclipse XDB C-18 (150 × 4.63 mm, 5 μm)Mobile Phase A: ACN Mobile Phase A: ACN Mobile Phase B: 0.1% Aq TFAMobile Phase B: 5 mM NH₄OAC Flow Rate: 1.0 mL/min Flow Rate: 1.0 mL/minMethod G: Method H: Column, Type, Size: Column, Type, Size: ChiralPakIC, 250 × 4.6 mm, 5μ Luna C-18 (150 × 2.0 mm, 5.0 μm) Mobile Phase A:0.1% TEA in n-Hexane Mobile Phase A: ACN Mobile Phase B: Ethanol MobilePhase B: 0.1% TFA in water A:B:: 70:30 Flow Rate: 1.0 mL/min Flow Rate:1.0 mL/min Method I: Method J: Column, Type, Size: Column, Type, Size:ChiralPak IC, 250 × 4.6 mm, 5μ ChiralPak IA, 250 × 4.6 mm, 5μ MobilePhase A: n-Hexane Mobile Phase A: n-Hexane Mobile Phase B: EthanolMobile Phase B: Ethanol A:B:: 80:20 A:B:: 75:25 Flow Rate: 1.0 mL/minFlow Rate: 1.0 mL/min Method K: Method L: Column, Type, Size: Column,Type, Size: ChiralPak IA, 250 × 4.6 mm, 5μ ChiralPak IC, 250 × 4.6 mm, 5μm Mobile Phase A: 0.1% DEA in n-Hexane Mobile Phase A: 0.1% DEA inn-Hexane Mobile Phase B: Methanol Mobile Phase B: Ethanol A:B:: 80:20A:B:: 60:40 Flow Rate: 1.0 mL/min Flow Rate: 1.0 mL/min Method M:Column, Type, Size: Sunfire C-18 (150 × 4.6 mm, 5 μm) Mobile Phase A:ACN Mobile Phase B: 50 mM NH₄HCO2 Flow Rate: 1.0 mL/min Method N:Column, Type, Size: Chiralpak IA (250 × 10 mm, 5 μm) Mobile Phase A: 15%EtOH Mobile Phase B: 30% IPA Mobile Phase C: 55% hexanes Flow Rate: 1.0mL/min

Solvent B: 0.025% TFA (Aq)

Flow Rate: 0.50 mL/min

Example 167: Metalloenzyme Activity A. Minimum Inhibitory Concentration(MIC)

Compounds were assessed for their ability to inhibit the growth ofcommon strains of fungus, C. albicans using a standardized procedure(CLSI M27-A2). Stock solutions of the test compounds and standards wereprepared in DMSO at 1600 μg/mL (C. albicans). Eleven, serial, one-halfdilutions of compounds were prepared in 96-well plates in RPMI+MOPS. Theassay concentration ranges were 1-0.001 μg/mL (C. albicans). Cellsuspensions of C. albicans were prepared and added to each well atconcentrations of approximately 3.7×10³ colony-forming-units permilliliter (cfu/mL). All testing was in duplicate. The inoculated plateswere incubated for approximately 48 h at 35±1° C. At the completion ofincubation the wells of each plate were evaluated visually for thepresence of fungal growth.

For fluconazole and the test compounds, the MIC was the concentration atwhich growth was significantly reduced (about 50% reduction). Forvoriconazole the M1C was the concentration which reduced C. albicansgrowth by 50% (per CLST, M27-A2). For QC purposes C. krusei isolate ATCC6258 (4.0×10³ cfu/mL) was included in the VOR assay. This isolate didnot exhibit trailing growth against voriconazole, therefore the MIC wasthe concentration at which growth was completely inhibited.

A. fumigatus MICs were determined at both 50% and 100% growth inhibitionfollowing CLSI guidelines at a concentration range of 64-0.062 μg/mL(CLSI M38-A2).

Results: Antifungal Activity

Example Candida MIC* Aspergillus MIC 2 0.004 8 5 0.016 8 9 ≤0.001 0.5101  0.25 2 108  0.062 4 Voriconazole 0.016 0.25 *Candida albicans MIC50(median inhibitory concentration) values expressed in ug/mL; Aspergillusfumigatus MIC50 values expressed in ug/mL.Compounds of the present invention inhibit growth of A. fumigatus in astandard 4-day mouse model. For example, oral administration of Compound(−)-9 at 20 mg/kg each of 4 days reduced mouse kidney fungal burden 84%compared to control.Compounds of the present invention inhibit growth of Septoria andPuccinia to protect plants from fungal infection (in vitro and inplanta). For example, Compounds 2, 3, and 21 exhibit a range ofMIC=0.25-1.0 ug/mL in a standard Septoria tritici MIC assay (ATCC 26517,CLSI protocol). Compounds of the present invention, for example Compound2, provide protection from fungal growth when applied at 50 ppm inplanta against both Septoria and Puccinia pathogens.

INCORPORATION BY REFERENCE

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents of the specificembodiments of the invention described herein. Such equivalents areintended with be encompassed by the following claims.

What is claimed: 1.-58. (canceled)
 59. A method of treating a subjectsuffering from Cryptococcosis, comprising administering to said subjectin need thereof, an effective amount of a compound of formula (I) orsalt thereof, wherein:

R₁ is halo; R₂ is halo; each R₃ is independently cyano, haloalkyl,alkoxy, halo, haloalkoxy, hydroxy, amino, —NR₆R₉, —SR₁₀, —C(O)R₁₀,optionally substituted haloalkyl, optionally substituted arylalkoxy,—C(O)NR₆R₇, —CH(OH)-haloalkyl, optionally substituted alkyl,hydroxyalkyl, alkoxyalkyl, isocyano, cycloalkylaminocarbonyl, optionallysubstituted aryloxyalkyl, optionally substituted arylalkylthio,haloalkylthio, optionally substituted arylalkylsulfonyl, optionallysubstituted arylalkylsulfinyl, optionally substituted heteroarylalkoxy,optionally substituted arylthioalkyl, or haloalkylcarbonyl; n is 0, 1, 2or 3; R₄ is aryl optionally substituted with 0, 1, 2 or 3 independentR₈; R₅ is H, alkyl, phosphato, phosphito, alkoxyphosphato, or —C(O)alkyloptionally substituted with 1 or 2 amino; R₆ is independently H oralkyl; R₇ is independently H, optionally substituted alkyl, optionallysubstituted haloalkyl, or optionally substituted arylalkyl; each R₈ isindependently cyano, haloalkyl, alkoxy, halo, or haloalkoxy; each R₉ isindependently H, alkyl, —C(O)alkyl, —C(O)H, —C(O)haloalkyl, optionallysubstituted arylalkyl, or optionally substituted haloalkyl; each R₁₀ isindependently H, optionally substituted alkyl, optionally substitutedaryl, optionally substituted heterocycloalkyl, or optionally substitutedarylalkyl; Ar₂ is

R₁₁ is optionally substituted phenyl, optionally substituted alkyl,optionally substituted thienyl, pyrrolyl, furanyl, optionallysubstituted pyridyl, —CH(OH)-alkyl, —CH(OH)-haloalkyl, optionallysubstituted arylalkyl, optionally substituted aryloxyalkyl, haloalkyl,haloalkoxyalkyl, optionally substituted indolyl, optionally substitutedbenzofuranyl, heterocycloalkyl, or

R₁₂ is R₄, —C(O)R₄, —C(O)R₇, —SO₂R₄; MBG is optionally substitutedtetrazolyl, optionally substituted triazolyl, optionally substitutedoxazolyl, optionally substituted pyrimidinyl, optionally substitutedthiazolyl, or optionally substituted pyrazolyl.
 60. The method of claim59, wherein the disorder or disease is associated with Cryptococcusneoformans.
 61. (canceled)
 62. (canceled)
 63. The method of claim 59,wherein the subject is an animal other than a human.
 64. The method ofclaim 59, wherein the subject is a human.
 65. The method of claim 59,wherein R₁ is fluoro.
 66. The method of claim 59, wherein R₂ is fluoro.67. The method of claim 59, wherein R₁ and R₂ are fluoro.
 68. The methodof claim 59, wherein R₄ is phenyl optionally substituted with 0, 1, 2 or3 independent R₈.
 69. The method of claim 59, wherein R₄ is phenyloptionally substituted with 0, 1, 2 or 3 independent halo.
 70. Themethod of claim 59, wherein R₄ is phenyl optionally substituted with 0,1, 2 or 3 independent fluoro.
 71. The method of claim 59, wherein R₄ is2,4-difluorophenyl.
 72. The method of claim 59, wherein R₅ is H.
 73. Themethod of claim 59, wherein R₅ is amino substituted acyl.
 74. The methodof claim 59, wherein R₅ is phosphato.
 75. The method of claim 59,wherein: R₁ is fluoro; R₂ is fluoro; R₄ is 2,4-difluorophenyl; R₅ is H;Ar₂ is

and MBG is 1-tetrazolyl.
 76. The method of claim 75, wherein: R₁₁ isphenyl, thienyl, arylalkyl, aryloxyalkyl, each optionally substitutedwith independent R₃; each R₃ is independently cyano, haloalkyl, halo,haloalkoxy, optionally substituted arylalkoxy, haloalkylaminocarbonyl,optionally substituted arylalkylaminocarbonyl; and n is 1 or
 2. 77. Themethod of claim 75, wherein: R₁₁ is phenyl, thienyl, arylalkyl,aryloxyalkyl, each optionally substituted with independent R₃; each R₃is independently cyano, haloalkyl, halo, haloalkoxy, optionallysubstituted arylalkoxy, haloalkylaminocarbonyl, optionally substitutedarylalkylaminocarbonyl; and n is
 1. 78. The method of claim 75, wherein:R₁₁ is phenyl optionally substituted with independent R₃; each R₃ isindependently cyano, haloalkyl, halo; and n is 1 or
 2. 79. The method ofclaim 75, wherein: R₁₁ is thienyl optionally substituted withindependent R₃; each R₃ is independently haloalkylaminocarbonyl,optionally substituted arylalkylaminocarbonyl; and n is 1 or
 2. 80. Themethod of claim 59, wherein the compound is one of:2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(phenylethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(1);1-(5-((4-Chlorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(2);2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(3);2-(2,4-Difluorophenyl)-1-(5-((2,4-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(4);2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(trifluoromethyl)phenyl)ethynyl)pyridin-2-yl)propan-2-ol (5);5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N-(4-fluorobenzyl)thiophene-2-carboxamide (6);4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl) pyridin-3-yl) ethynyl) phenoxy) methyl)-2-fluorobenzonitrile(7);4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)benzonitrile(8);2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl) ethynyl) pyridin-2-yl)propan-2-ol (9);2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((1-methyl-1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(10);2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)thiophen-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(11);2-(2,4-Difluorophenyl)-1-(6-((3,4-difluorophenyl)ethynyl)pyridazin-3-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(12);4-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)but-3-yn-2-ol(13);2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoro-1-hydroxyethyl)thiophen-2-yl)ethynyl)pyridin-2-yl)propan-2-ol(14);2-(2,4-difluorophenyl)-1-(5-((3,4-difluorophenyl)ethynyl)pyrazin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(15);2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoro-1-hydroxyethyl)furan-2-yl)ethynyl)pyridin-2-yl)propan-2-ol (16);2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-(3-fluorophenyl)prop-1-yn-1-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(17);2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-(4-fluorophenoxy)prop-1-yn-1-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(18);2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((1-(4-fluorophenyl)piperidin-4-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(19);1-(5-((4-((4-Cyanobenzyl)oxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-yl dihydrogen phosphate (20);1-(5-((3-chlorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(21);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-(trifluoromethyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(22);2-(2,4-difluorophenyl)-1-(5-(3,3-difluoroprop-1-ynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(23);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(24);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(25);1-(5-((4-(difluoromethyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(26);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-methylphenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(27);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((3-fluoropyridin-2-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(28);1-(5-((5-chlorothiophen-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(29);2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(trifluoromethyl)thiophen-2-yl)ethynyl)pyridin-2-yl)propan-2-ol(30);2-(2,4-difluorophenyl)-1-(5-((3,5-difluoropyridin-2-yl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(31);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((5-fluoropyridin-2-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(32);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((6-fluoropyridin-3-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(33);2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(trifluoromethoxy)phenyl)ethynyl)pyridin-2-yl)propan-2-ol(34);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-methoxyphenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(35);2-(2,4-difluorophenyl)-1-(5-((2,6-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(36);2-(2,4-difluorophenyl)-1-(5-((3,4-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(37);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((5-methylthiophen-2-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(38);1-(5-((4-(1,1-difluoroethyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(39);1-(5-((4-(difluoromethoxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(40);2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(trifluoromethylthio)phenyl)ethynyl)pyridin-2-yl)propan-2-ol(41);1-(5-((4-chloro-3-fluorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(42);2-(4-chloro-2-fluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(43);1,1-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(44);2-(2,5-difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(45);2-(3,4-difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(46);1-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenyl)ethanone(47);2-(2,4-difluorophenyl)-1,1-difluoro-1-(6-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(48);2-(2,4-difluorophenyl)-1,1-difluoro-1-(6-((4-fluorophenyl)ethynyl)pyridazin-3-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(49);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(hydroxymethyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(50);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(methoxymethyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(51);4-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)-1,1,1-trifluorobut-3-yn-2-ol(52);1-(5-((5-bromothiophen-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(53);1-(5-((5-(difluoromethyl)thiophen-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(54);1-(5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)thiophen-2-yl)-2,2,2-trifluoroethanone(55);2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((1-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)propan-2-ol(56);2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(3-(2,2,2-trifluoroethoxy)prop-1-ynyl)pyridin-2-yl)propan-2-ol(57);2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(thiophen-2-ylethynyl)pyridin-2-yl)propan-2-ol(58);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-(methylamino)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(59);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(methylamino)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(60);2-(2,4-difluorophenyl)-1-(5-((3,4-difluorophenyl)ethynyl)thiophen-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(61);2-(2,4-difluorophenyl)-1-(5-((4-(dimethylamino)phenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(62);1-(5-((1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(63);1-(5-((4-(difluoromethyl)-3-fluorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(64);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(3-(3-fluorophenyl)prop-1-ynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(65);1-(5-((1-(difluoromethyl)-1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(66);2-(2,4-difluorophenyl)-1-(5-((2,5-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(67);N-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenyl)formamide(68);4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzonitrile(69);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-isocyanophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(70);3-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzonitrile(71);1-(5-((5-bromofuran-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(72);4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-3-fluorobenzonitrile(73);4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-2-fluorobenzonitrile(74);3-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-4-fluorobenzonitrile(75);1-(5-((5-(difluoromethyl)furan-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(76);2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoroethyl)thiophen-2-yl)ethynyl)pyridin-2-yl)propan-2-ol(77);1-(5-((4-aminophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(78);N-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenyl)-2,2,2-trifluoroacetamide(79);2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(2,2,2-trifluoroethylamino)phenyl)ethynyl)pyridin-2-yl)propan-2-ol(80);4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenol(81);4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzamide(82);1-(5-((4-amino-2-fluorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(83);N-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenyl)acetamide(84);1-(5-(3-(2,4-difluorophenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(85);4-(3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)prop-2-ynyloxy)benzonitrile(86);1-(5-((1H-indol-5-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(87);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-fluorobenzylamino)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(88);1-(5-(benzofuran-5-ylethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(89);2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(2,2,2-trifluoroethyl)phenyl)ethynyl)pyridin-2-yl)propan-2-ol(90);4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N-(2,2,2-trifluoroethyl)benzamide(91);(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenyl)(pyrrolidin-1-yl)methanone(92);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-fluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(93);5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide(94);(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)piperidin-1-yl)(4-fluorophenyl)methanone(95);1-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)piperidin-1-yl)-2,2,2-trifluoroethanone(96);2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((3-(2,2,2-trifluoroethoxy)phenyl)ethynyl)pyridin-2-yl)propan-2-ol(97);3-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N-(2,2,2-trifluoroethyl)benzamide(98);1,1-difluoro-2-(4-fluorophenyl)-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(99);3-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)benzonitrile(100);2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(4-(trifluoromethoxy)benzyloxy)phenyl)ethynyl)pyridin-2-yl)propan-2-ol(101);4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-3-fluorobenzonitrile(102);3-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-4-fluorobenzonitrile(103);2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(3-(trifluoromethoxy)benzyloxy)phenyl)ethynyl)pyridin-2-yl)propan-2-ol(104);1-(5-((4-(2,4-difluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(105);1-(5-((4-(3,4-difluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(106);1-(5-((4-(4-chlorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(107);1-(5-((4-(4-chloro-2-fluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(108);4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-N-methylbenzamide(109);6-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)nicotinonitrile(110);2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(thiazol-2-ylmethoxy)phenyl)ethynyl)pyridin-2-yl)propan-2-ol(111);5-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-2-fluorobenzonitrile(112);1-(5-((4-(2,3-difluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(113);1-(5-(3-(4-chlorophenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(114);4-(3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)prop-2-ynyloxy)-3-fluorobenzonitrile(115);4-(3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)prop-2-ynyloxy)-2-fluorobenzonitrile(116);1-(5-(3-(4-chloro-2-fluorophenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(117);1-(5-(3-(4-(difluoromethyl)phenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(118);5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N-(3-fluorobenzyl)thiophene-2-carboxamide(119);N-(3-cyanobenzyl)-5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)thiophene-2-carboxamide(120);N-(4-cyanobenzyl)-5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)thiophene-2-carboxamide(121);5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N-(4-(trifluoromethyl)benzyl)thiophene-2-carboxamide(122);(5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)thiophen-2-yl)(morpholino)methanone(123);(5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)thiophen-2-yl)(pyrrolidin-1-yl)methanone(124);5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N-(4-(methylsulfonyl)benzyl)thiophene-2-carboxamide(125);3-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-2-fluorobenzonitrile(126);3-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-5-fluorobenzonitrile(127);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(piperidin-4-ylethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(128);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((1-(4-fluorophenylsulfonyl)piperidin-4-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(129);1-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenyl)-2,2,3,3,3-pentafluoropropan-1-ol(130);4-((4-((6-(2-(2,5-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-2-fluorobenzonitrile(131);4-((4-((6-(2-(4-chloro-2-fluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-2-fluorobenzonitrile(132);4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenylthio)methyl)-2-fluorobenzonitrile(133);4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenylsulfinyl)methyl)-2-fluorobenzonitrile(134);4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenylsulfonyl)methyl)-2-fluorobenzonitrile(135);4-((4-((6-(2-(2,5-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)benzonitrile(136);4-((4-((6-(2-(4-chloro-2-fluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)benzonitrile(137);4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenylthio)methyl)benzonitrile(138);5-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)picolinonitrile(139);1-(5-((4-(4-cyanobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-yldihydrogen phosphate (140);5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl)ethynyl)-N-(4-fluorobenzyl)thiophene-2-carboxamide(141);4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)benzonitrile(142);4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)-2-fluorobenzonitrile(143);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-yl2-aminoacetate hydrochloride (144);(2S)-2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-yl2,6-diaminohexanoate dihydrochloride (145);1-(5-((4-(4-chloro-3-fluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(146);1-(5-((4-(biphenyl-4-ylmethoxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(147);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-methylbenzyloxy)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(148);2-(2,4-difluorophenyl)-1-(5-((4-(4-ethylbenzyloxy)phenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(149);1-(5-((4-(4-(difluoromethyl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(150);(+)-1-(5-((4-(4-(difluoromethyl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol((+)-150);2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(4-(trifluoromethyl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)propan-2-ol(151);4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzyloxy)-3-fluorobenzonitrile(152);5-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzyloxy)-2-fluorobenzonitrile(153);1-(5-((4-(4-(1H-pyrazol-1-yl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(154);4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzyloxy)benzonitrile(155);1-(5-((4-((4-chlorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(156);1-(5-((4-((biphenyl-4-yloxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(157);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-(oxazol-2-yl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(158);2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-((4-fluorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol(159);1-(5-((4-((3,4-difluorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(160);1-(5-((4-((4-(difluoromethyl)phenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(161);4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzylthio)benzonitrile(162);5-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)thiophene-2-carbonitrile(163);4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzyloxy)-2-fluorobenzonitrile(164);1-(5-((4-((4-chloro-3-fluorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(165);4-((3-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)benzonitrile(166); or salt thereof.
 81. The method of claim 59, wherein the compoundis one of:4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl) pyridin-3-yl) ethynyl) phenoxy) methyl)-2-fluorobenzonitrile(7), or salt thereof; ori4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzonitrile (8), orsalt thereof.
 82. A compound that is4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl) pyridin-3-yl) ethynyl) phenoxy) methyl)-2-fluorobenzonitrile(7), or salt thereof.
 83. A compound that is4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzonitrile (8), orsalt thereof.